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The Impact of Diabetic Foot Problems on Health-related Quality of Life of People with Diabetes
by
Fernanda Naomi Inagaki Nagase
A thesis submitted in partial fulfillment of the requirements for the degree of
Master of Science
in
Health Technology Assessment
School of Public Health
University of Alberta
© Fernanda Naomi Inagaki Nagase, 2016
ii
Abstract
People with diabetes are at a greater risk of developing foot complications and this chronic
condition continues to be the leading cause of non-traumatic amputations in Canada. The
purpose of this thesis was to examine the impact diabetic foot problems have on health-related
quality of life of people with diabetes, through a systematic review and a cross-sectional analysis
of a population with type 2 diabetes living in Alberta. Both studies found an association between
reduced HRQOL and diabetic foot problems. Mainly, lower physical health, measured with the
SF-36/12, correlated with the severity of foot complications in people with diabetes. The highest
decrement on mental health was found in people with diabetes reporting ulceration, which also
had the lowest index score, measured with the EQ-5D-5L in the cross-sectional study.
Individuals with either or both risk factors for diabetic foot problems, neuropathy and peripheral
vascular disease were also associated with lower physical, mental and perceived health compared
to individuals with diabetes but no foot complications.
This research implies that interventions to promote better quality of life are needed throughout
the different stages of foot problems in people with diabetes.
iii
Acknowledgments
This thesis is a result of hard work and the contribution of several people. First, I would like to
express my sincere gratitude to my supervisor Dr. Arto Ohinmaa for accepting me as his mentee
and his support during this whole process. I would also like to thank my committee members, Dr.
Jeffrey A. Johnson and Dr. Thanh Nguyen for their assistance and shared expertise.
I must also acknowledge Carolina G. Freitas, from Cochrane Brazil, and Álvaro M. Nishikawa,
from University of São Paulo, as the second reviewers for the selection, data extraction and
quality assessment of studies included in the systematic review of this thesis. Without their
assistance and inputs, the conduction of the project described in the second chapter would not
have been possible.
I want to thank Dr. Fatima Al Sayah, from ACHORD, who is the administrator of the ABCD
cohort study. I am grateful for her valuable comments and assistance on how to manage and
analyze the data. I also appreciate her suggestions on the conduction and writing process of the
third chapter.
Finally, many thanks to my friends and those who, unfortunately, are no longer with us. Thanks
to the kindness and friendship from the people who I had the opportunity to meet in Canada. I
especially want to thank all of my friends from Colégio Etapa, Farmácia USP and design UNESP,
who encourage me and listen to all my frustrations. Lastly, I wish to acknowledge the two people
who I love the most and are my greatest source of inspiration, my father, Édio M. Nagase and,
my mother, Alice Inagaki. Without them, my dreams would have remained only in my head.
iv
Table of Contents
Chapter 1. Introduction ........................................................................................................... 1
1.1. Background ..................................................................................................................... 2
1.2. Economic Burden of Diabetic Foot Disease ................................................................... 2
1.3. Diabetic foot: definition and clinical pathway ................................................................ 3
1.4. Prevalence, incidence and clinical burden of diabetic foot ............................................. 4
1.5. Health-related Quality of Life (HRQOL) ....................................................................... 6
1.6. Objectives ....................................................................................................................... 9
1.7. References ..................................................................................................................... 10
Chapter 2. Systematic Review of Foot Problems and Health-related Quality of Life of
People with Diabetes ................................................................................................................... 17
2.1. Introduction ................................................................................................................... 17
2.2. Methods......................................................................................................................... 18
2.2.1. Eligibility criteria .............................................................................................................. 18
2.2.2. Search Strategy ................................................................................................................. 19
2.2.3. Selection Process, Data Extraction and Quality Assessment ............................................ 20
2.2.4. Meta-analysis .................................................................................................................... 21
2.3. Results ........................................................................................................................... 22
2.3.1. Description and Quality Assessment of Included Studies ................................................ 26
2.3.2. Participants........................................................................................................................ 26
2.3.3. Health-related Quality of Life ........................................................................................... 26
2.3.4. Meta-analysis .................................................................................................................... 28
2.4. Discussion ..................................................................................................................... 30
2.5. Conclusion .................................................................................................................... 33
2.6. References ..................................................................................................................... 34
Chapter 3. Health-related Quality of Life of Adults with Type 2 Diabetes Reporting Foot
Problems in Alberta .................................................................................................................... 39
3.1. Introduction ................................................................................................................... 39
3.2. Methods......................................................................................................................... 40
3.2.1. Study Population ............................................................................................................... 40
3.2.2. Measures ........................................................................................................................... 40
v
3.2.3. Health-related Quality of Life ........................................................................................... 40
3.2.4. Statistical Analysis ............................................................................................................ 41
3.2.5. Ethics ................................................................................................................................ 42
3.3. Results ........................................................................................................................... 42
3.3.1. General Characteristics of Participants ............................................................................. 42
3.3.2. Health-related Quality of Life ........................................................................................... 44
3.3.3. Multiple Linear Regression Analysis ................................................................................ 48
3.4. Discussion ..................................................................................................................... 48
3.5. Conclusion .................................................................................................................... 52
3.6. References ..................................................................................................................... 53
Chapter 4. General Discussion and Conclusion .................................................................. 58
4.1. Summary of Findings .................................................................................................... 58
4.2. Discussion ..................................................................................................................... 59
4.3. Conclusion and Future Research .................................................................................. 62
4.4. References ..................................................................................................................... 64
References .................................................................................................................................... 67
Appendix ...................................................................................................................................... 82
vi
List of Tables
Table 2.1. Characteristics of included studies .............................................................................. 23
Table 2.2. Meta-analysis of SF-36 and SF-12 domains and summary scores comparing
participants with and without foot ulcer ....................................................................................... 29
Table 2.3. Meta-analysis of SF-36 and SF-12 domains and summary scores comparing
participants with and without peripheral neuropathy.................................................................... 30
Table 3.1. Socio-demographic and clinical characteristics of the included and excluded
respondents ................................................................................................................................... 43
Table 3.2. Results of the SF-12v2 and proportion of response of the EQ-5D-5L ........................ 44
Table 3.3. Results of multiple linear regression of SF-12v2 (MCS and PCS) ............................. 46
Table 3.4. Results of multiple linear regression of EQ-5D-5L index and PAID-5 score ............. 47
vii
List of Figures
Figure 2.1. Search strategy used on Embase................................................................................. 20
Figure 2.2. PRISMA flowchart of the systematic review search .................................................. 22
viii
List of Abbreviations
ABCD study Alberta's Caring for Diabetes study
ABI Ankle Brachial Index
BMI Body Mass Index
BP Bodily Pain
CINAHL Current Nursing and Allied Health Literature
DARTS Diabetes Audit and Research in Tayside Scotland
DCCT Diabetes Control and Complications Trial
DFU Diabetic Foot Ulcer
DQOL Diabetes Quality of Life
EPHPP Effective Public Health Practice Project
EQ-5D EuroQol 5-Dimension Questionnaire
EQ-5D-5L 5-level EuroQol 5-Dimension Questionnaire
FAAM Foot and Ankle Ability Measure
GH General Health
HbA1c Glycated Hemoglobin
HRQOL Health-related Quality of Life
HUI-3 Health Utility Index Mark 3
IDF International Diabetes Federation
IWGDF International Working Group on the Diabetic Foot
MCS Mental Component Summary
MEPS Medical Expenditure Panel Survey
ix
MH Mental Health
MID Minimal Important Difference
OECD Organization for Economic Co-operation and Development
PAID-5 Short Form of the Problem Areas in Diabetes Scale
PCS Physical Component Summary
PF Physical Functioning
PRISMA Preferred Reporting Items for Systematic Review and Meta-
analysis
PRISMA-P Preferred Reporting Items for Systematic Review and Meta-
analysis Protocols
PVD Peripheral Vascular Disease
RE Role Limitations due to Emotional Problems
RP Role Limitations due to Physical Problems
SF Social Functioning
SF-12 Medical Outcome Study 12-item Short Form Health Survey
SF-36 Medical Outcome Study 36-item Short Form Health Survey
SMD Standardized Mean Difference
UKPDS United Kingdom Prospective Diabetes Studies
VAS Visual Analogue Scale
VT Vitality
WHO World Health Organization
WHO-BREF World Health Organization Quality of Life
1
Chapter 1. Introduction
This thesis is in a paper format and in line with the guidelines from the Faculty of Graduate
Studies and Research, University of Alberta. The thesis is separated into 4 chapters:
Chapter 1. The introductory chapter of the thesis. It reports on the background, definitions,
prevalence, health-related quality of life, and economic burden of diabetic foot problems, and
objectives of the thesis.
Chapter 2. A manuscript of a systematic review on the impact that foot problems have on the
health-related quality of life (HRQOL) for people with diabetes.
Chapter 3. A manuscript on the impact foot problems have on health-related quality of life in
people with type 2 diabetes living in Alberta, Canada.
Chapter 4. The final chapter is the general discussion and conclusion of the thesis. It shows the
overall findings, their implications, strength and limitations of this thesis.
2
1.1. Background
Worldwide, 415 million people were diagnosed with diabetes in 2015 and it is expected that 1
out of 10 adults will have diabetes by 20401. The prevalence of this chronic condition is also on
the rise in Canada, which has one of the highest prevalence rates among the Organization for
Economic Co-operation and Development (OECD) countries1, 2
.
Diabetes represents a major economic burden in developed countries. The Canadian health
expenditure for this illness was estimated to be around US$ 14 billion in 20151. A conservative
economic model estimated that the direct and indirect costs of diabetes in Alberta were around
1.3 billion dollars in 2014 and by 2024 these costs could increase to 1.7 billion dollars3. The
increase in costs are mainly due to the rise on the prevalence of type 2 diabetes which represents
90 to 95% of diabetic cases2.
This chronic condition also represents a major clinical and societal burden. About 2.8% of all
causes of death in 2012 were attributed to diabetes, that ranked as the 6th
leading cause of
mortality in Canada4. The main reasons are its association with several complications, including
nerve damage, vision loss, cardiovascular disease and lower extremity problems, leading to
increase in morbidity and mortality. Moreover, all of these conditions require treatment during
an individual’s lifetime and continuous use of health-care resources5.
One of the most serious and costly consequences of diabetes are the development of foot
problems which, if not treated, can lead to amputation6.
1.2. Economic Burden of Diabetic Foot Disease
Diabetic-foot related complications represent a major cost for the health-care system as chronic
ulcers, if infected, require extensive treatment and in worst case scenario, lead to amputations, a
costly procedure. An international review published in 2005 estimated diabetic foot accounted
for 7% to 20% of total expenditure on diabetes7.
A recent study on economic burden of diabetic foot disease in Canada reported an hospitalization
rate due to diabetic foot ulcers of 88 per 100,000 population8. The authors estimated the total
cost of diabetic foot related problems in 2011 to be CND$547 millions8. However, this is
probably an underestimation since it does not account for outpatient visits and indirect costs such
3
as productivity loss. The addition of indirect costs could represent an addition of 8.7% to 18.7%
of total costs9.
1.3. Diabetic foot: definition and clinical pathway
The International Working Group on the Diabetic Foot (IWGDF) defines diabetic foot as the
“infection, ulceration or destruction of tissues associated with neuropathy and/ or peripheral
artery disease in the lower extremity of people with diabetes”10
. In fact, the main risk factors for
diabetic foot ulcers are peripheral neuropathy, foot deformities (i.e. Charcot arthropathy), trauma
and peripheral vascular disease11, 12
. Reiber et al. identified that the combination of loss of
sensation, foot deformity and trauma was the most common pathway to foot ulceration in
diabetes13
.
Neuropathies are the most prevalent complications of diabetes and the main risk factors are poor
glycemic control and diabetes duration14-17
. Different nerves are affected by neuropathy resulting
in a range of symptoms and clinical signs14
. The most common types of this chronic condition
are sensorimotor diabetic peripheral neuropathy (or simply peripheral neuropathy) and
autonomic neuropathy18, 19
.
The majority of peripheral neuropathy cases in diabetes are asymptomatic, but around 15-25%
will develop symptoms ranging from paraesthesia to hyperaesthesia, with symptoms of sharp and
burning pain20
. All these manifestations are accompanied by loss of protective sensation18
. As a
results, subjects are more likely to develop ulcers, though cohort studies on this matter had
different results, mainly due to different methodologies for measuring neuropathy21
. A recent
meta-analysis reported that patients with a loss of sensation related to neuropathy had
approximately 3.2 times higher odds of ulceration than those without neuropathy22
. Peripheral
neuropathies are also associated with weakness and muscle atrophy which also increases the risk
for ulceration23
.
The second most common type of neuropathy is the autonomic neuropathy, which can result in
reduced sweating and dryer skin that make feet more prone to callus and increase of foot
temperature in the absences of peripheral vascular disease (PVD)18, 20
. Both types of neuropathy
are often found in the clinical pathway of ulceration18
.
4
Another consequence of neuropathy is the development of Charcot arthropathy, a foot deformity
that begins with signs of local inflammations that can eventually lead to bone and joint
destruction10, 24
. This continuous process triggers foot abnormalities which increase the risk of
diabetic foot ulcers, particularly when associated with loss of protective sensation24, 25
.
The second most important factor in diabetic foot ulcers is the presence of PVD, a condition in
which the blood flow of lower extremities is obstructed. The diabetic population are 2 to 8 times
more likely to have PVD and at a younger age and with more rapid progression of the disease
than non-diabetes population26, 27
.
The diagnosis and management of PVD is extremely important because, beyond being a risk
factor, studies have found worse outcomes such as longer ulcer duration, and higher prevalence
of amputation and mortality in which PVD was present with ulceration20, 28, 29
. In addition, PVD
is also a risk factor for cardiovascular and cerebrovascular diseases27
. However, the diagnosis of
PVD is challenging as most diabetic people are asymptomatic and may have a false ankle
brachial index (ABI) measurement because of arterial calcification30-32
. The management of PVD
in diabetes also poses another challenge as currently there are no guidelines or studies on
revascularization or treatment on these specific conditions27, 33
.
Other risk factors of diabetic foot ulcers include age, previous history of ulcer, poor glycemic
control, visual impairment and diabetes duration. As a results of these different factors, diabetic
foot ulcers can vary in clinical signs, symptoms, size and duration. Though the majority of foot
ulcers will heal, around 10 to 15% will persist and 5 to 24% of them will require amputation26
.
Worse outcomes are associated with the presence of infection which occurs after ulceration18
.
Around 85% of amputations are preceded by foot ulcerations in diabetes and most cases are
preventable34
.
1.4. Prevalence, incidence and clinical burden of diabetic foot
The accurate prevalence of diabetic neuropathy is unclear because of variation in study settings
and instruments used for diagnosing neuropathy. A compilation of population-based studies
found that the prevalence of neuropathy ranges in a population of type 1 and type 2 diabetes
from 12.8% to 54.0% and 13.1% to 45.0%, respectively35
. Within this range, the prevalence of
5
diabetic neuropathy in Canada was estimated to be around 37.5% of the population with diabetes
in 200836, 37
. A study conducted by Pirart J reported a prevalence of 50% of neuropathy in a
cohort of diabetic patients followed for 25 years38
. An accurate measure on incidence of this
condition is also unclear due to the previous reasons and the fact that many cases are
asymptomatic and underdiagnosed. A review based on data from the United Kingdom
Prospective Diabetes Study (UKPDS) and the Diabetes Control and Complications Trial (DCCT)
reported an annual incidence of neuropathy in a diabetes population to be approximately 2%39
.
Accurate measurements on the prevalence and incidence of PVD in diabetic individuals are also
difficult to find. Studies on this area usually measure the prevalence within the general
population and do not report it specifically for diabetes. Other methodological issues include
variation on the definition and diagnosis of PVD and settings which the sample was drawn27
. The
Fremantle Diabetes Study, a large population-based study conducted in Australia, reported a
13.6% prevalence of PVD in type 2 diabetes40
. Another large population-based study, the
Framingham Heart study, found a prevalence of 20% of PVD in diabetes, although authors
suggest that this is an underestimation as they only measured patients presenting PVD
symptoms41
. A Scottish based study, the DARTS study, found the incidence of PVD in type 1
and type 2 diabetes to be 5.5 and 13.6 per 1,000 subjects, respectively42
. In Canada, PVD
remains underdiagnosed and the true prevalence of the disease in the population remains
unclear43
.
A serious consequence of diabetic neuropathy and PVD along with environmental factors is the
diabetic foot ulcer (DFU). Studies suggest that the prevalence of ulceration in the diabetic
population is from 4% to 10% and the annual incidence could range from 1.0% to 4.1%44, 45
. The
incidence becomes higher (5% to 7%) in individuals with neuropathy. The lifetime risk of foot
ulcers in individuals with diabetes could be 15% to 25%45, 46
. Based on these estimates, around
42,976 people with diabetes in Alberta had experienced a foot ulcer in 201447
. On a recent study
using administrative data across Canada, the prevalence and incidence of diabetic foot ulcers in
Alberta in 2011 were 1.9% and 1.0%, respectively8, 37
. These results were higher compared to the
national prevalence of 1.4% and incidence of 0.8%, though these numbers are probably an
underestimation of the true values8, 37
.
6
The prognosis of diabetic foot ulcers is poor, as those with previous ulceration are at higher risk
of developing another ulcer. One meta-analysis also reported that the odds of diabetic foot ulcer
is 6.6 times higher in individuals with previous history of ulceration or amputation22
. A Swedish
cohort study of 558 patients with healed foot ulcers found 70% of them had a new foot ulcer and
12% had an amputation after 5 years of follow up48
. The prognosis of foot ulcers is also poor
because of the high mortality among these subjects. Two cohort studies found a mortality rate
ranging from 42 to 44% after 5 years, regardless of presence of amputation47, 48
.
Diabetic foot ulcers, if not treated, can lead to amputation, another serious sequelae of diabetes.
In Canada, the diabetic population was 20 times more likely to have an amputation compared to
the general population2. Between 2011-2012, diabetes accounted for 60.3% of amputations
performed in hospitals in the country49
. Consequently, diabetes is the leading cause of non-
traumatic amputations2. The rates of amputation are different across Canada as rates of diabetes
and amputations are found to be higher among First-Nations49
. A publication from Alberta
Health reported that since 2004, the First Nations population had an amputation rate three times
higher than non-First Nations50
.
Amputation represents a major clinical burden with high mortality rates. A study from 1988
found a mortality rate of 50% after two years on diabetic patients undergoing amputation51
. More
recent studies found that after five years the cumulative mortality rate ranges from 68% to
78.7%52, 53
. Patients undergoing amputation also reported higher morbidity and lower quality of
life compared to the general diabetic population2.
1.5. Health-related Quality of Life (HRQOL)
The definition of health, according to the World Health Organization (WHO) is “a state of
complete physical, mental and social well-being and not merely the absence of disease or
infirmity”54
.
There have been some criticisms on the definition of health by WHO as it is very broad and it
has not been updated since its creation (1948). Most argue that it does not account for the current
state of increased prevalence of chronic conditions such as diabetes in which there is no cure and
the “state of complete” and “absence of disease” cannot be achieved55
. It also does not take into
7
account the patient’s perspective and its ability to adapt and live with the disease55
. Nonetheless,
the definition raises awareness on the importance of measuring different domains of health such
as mental, social and physical function.
The need for improving measurements on health and the acknowledgement of the limitations of
the concept of health in chronic conditions are some of the reasons that lead to the development
of research on health-related quality of life (HRQOL).
HRQOL is a multi-dimensional concept that is mainly concerned with a person’s well-being
through different health domains (physical, mental and social functioning)56
. One study reported
that in 2005 over 5,300 articles were published on HRQOL, an increase of 10% on publication
from the previous year, demonstrating the increase on researchers interest on HRQOL57
.
Clinical measurements such as HbA1c or presence of complications in diabetes does not fully
capture the health status of the diabetic population. It does not take into consideration a patient’s
perception on health and their capability to adapt to the disease58
. Thus, the use and importance
of HRQOL has increased in this area. There are three main purposes for measuring HRQOL: (1)
to monitor the health status of a population; (2) to measure effectiveness of an intervention; (3)
to use as a potential predictor for health outcomes and death.
Studies have shown that self-rated health and HRQOL predict mortality in diabetes and other
disease-specific populations (i.e. cancer)59-61
. Other studies suggest the potential use of HRQOL
as a predictor of morbidity, health-care utilization and adverse health events62-65
. Clarke et al62
and Li et al64
found that HRQOL measures predicted respectively, cardiovascular
hospitalizations and all-cause hospitalizations in a diabetic population. Both studies utilized
different study settings, type of diabetes and different HRQOL instruments. In addition, the
Eurodiale study found that the mobility domain of the EQ-5D can be used as a predictor of death
and amputations which could also be associated with higher hospitalization rates65
.
The diabetic population has rated their health lower than the general population but higher
compared to some other chronic diseases66
. However, when combined with other diabetic
complications67
such as foot ulcers and amputations, we can see a higher decrement on HRQOL,
especially in the physical domain68-71
.
8
One literature review from 2004 included qualitative and quantitative measures of HRQOL in
diabetes but was mainly focused on qualitative results69
. The study found that diabetic patients
with foot ulcer had lower HRQOL than diabetic amputees69
. It also found that peripheral
neuropathy and negative feelings toward the lower extremities increased probabilities of
development of ulcers69
. However, it is important to notice that these observations came from a
limited number of studies and the author did not mention how the literature search was
conducted.
In 2005, Goodridge et al published a literature review on HRQOL in diabetic foot ulcers72
. The
search was conducted with a limited search strategy and in two electronic databases: The Current
Nursing and Allied Health Literature (CINAHL) and Medline72
. The review included qualitative
and quantitative studies published until 200472
. Both type of studies reported the impact of ulcer
on physical functioning, social and psychological well-being72
. The authors also concluded there
was a lack of studies on diabetic foot ulcers, in particular in the number of longitudinal studies72
.
Both literature reviews were mainly focused on different stages of diabetic foot ulcers (i.e.
healed, unhealed) and amputations as there were no descriptions on impact of PVD and
peripheral neuropathy on HRQOL in the diabetic population. In addition, they were prone to
meta-bias as they did not follow steps of guidelines on systematic review (i.e. PRSIMA73
) and
were likely conducted by just one reviewer and limited electronic databases.
Hogg et al conducted a systematic review of studies, published until February 2011, assessing
the validity and reliability of quantitative HRQOL measures on diabetic foot68
. As a secondary
aim, authors assessed the impact of HRQOL on patients with diabetic foot using the same
included studies68
. The authors reported decrements on HRQOL of diabetic patients with ulcer,
regardless of it etiology, and their scores were lower compared to those without foot problems,
healed ulcers and with minor amputation68
. Decrements on health were also found in major
amputations and symptomatic neuropathies68
. The systematic review concluded lacked
longitudinal studies and consequently provided limited proof of the causal relationship of
diabetic foot and HRQOL68
.
The systematic review68
did not result in any reports on quality of life of the diabetic population
living in Alberta, Canada. It also did not describe the impact of PVD on HRQOL of diabetic
individuals as this foot problem was not included in the systematic search, though it is an
9
important risk factor for ulceration and can have an impact on physical functioning. The authors
did not describe whether the systematic review was according to guidelines such as the Cochrane
handbook on systematic review. Thus, it is unclear how the selection, extraction and quality
assessment were conducted and the presence or not of more than one reviewer during this
process.
With the limitations of the current reviews, rapid increase of studies on HRQOL and changes on
treatments for diabetic foot, it is important to improve the quality of systematic reviews and keep
the information up to date. Additionally, studies on HRQOL of people with type 2 diabetes with
or without foot problems are lacking in Alberta.
1.6. Objectives
The objectives of this thesis were to:
(1) Identify and synthesize the current evidence on the impact of diabetic foot problems on
health-related quality of life through a systematic review.
(2) Assess and compare the health-related quality of life of people with type 2 diabetes with
or without foot problems living in Alberta.
10
1.7. References
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2. Public Health Agency of Canada. Diabetes in Canada: Facts and figures from a public
health perspective. Ottawa2011.
3. Canadian Diabetes Association. Diabetes in Alberta2014.
4. Statistics Canada. CANSIM table 102-0561: Leading cause of death by sex (both
sexes)2015.
5. Kontodimopoulos N, Pappa E, Chadjiapostolou Z, Arvanitaki E, Papadopoulos AA,
Niakas D. Comparing the sensitivity of EQ-5D, SF-6D and 15D utilities to the specific effect of
diabetic complications. European Journal of Health Economics. 2012;13:111-120.
6. Vileikyte L. Diabetic foot ulcers: a quality of life issue. Diabetes Metab Res Rev.
2001;17:246-249.
7. Boulton AJM, Vileikyte L, Ragnarson-Tennvall G, Apelqvist J. The global burden of
diabetic foot disease. Lancet. 2005;366:1719-1724.
8. Hopkins RB, Burke N, Harlock J, Jegathisawaran J, Goeree R. Economic burden of
illness associated with diabetic foot ulcers in Canada. Bmc Health Services Research. 2015;15:9.
9. Canadian Diabetes Association. Ontario Report2015.
10. International Working Group on the Diabetic Foot. Definition & Criteria 20152015.
11. Boulton AJM. The diabetic foot: from art to science - The 18th Camillo Golgi lecture.
Diabetologia. 2004;47:1343-1353.
12. Tennvall GR, Apelqvist J. Prevention of diabetes-related foot ulcers and amputations: a
cost-utility analysis based on Markov model simulations. Diabetologia. 2001;44:2077-2087.
13. Reiber GE, Vileikyte L, Boyko EJ, et al. Causal pathways for incident lower-extremity
ulcers in patients with diabetes from two settings. Diabetes Care. 1999;22:157-162.
14. Boulton AJM, Malik RA, Arezzo JC, Sosenko JM. Diabetic somatic neuropathies.
Diabetes Care. 2004;27:1458-1486.
11
15. Vinik A, Mitchell B, Leichter S, Wagner A, O'Brian J, Georges L. Epidemiology of the
complications of diabetes. In: Press CU, ed. Diabetes: Clinical Science in Practice.
Cambridge1995:221-287.
16. Holzer SES, Camerota A, Martens L, Cuerdon T, Crystal-Peters J, Zagari M. Costs and
duration of care for lower extremity ulcers in patients with diabetes. Clinical Therapeutics.
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17. Pinzur MS. Diabetic peripheral neuropathy. Foot Ankle Clin. 2011;16:345-349.
18. Boulton AJM. The Pathway to Foot Ulceration in Diabetes. Medical Clinics of North
America. 2013;97:775-+.
19. Kempler P. Types, clinical presentation and diagnosis of somatic neuropathy.
Neuropathies: Springer Berlin Heidelberg New York; 2002:53-78.
20. Katsilambros N, Makrilakis K, Tentolouris N, Tsapogas P. Diabetic foot. European
Manual of Medicine: Vascular Surgery. Leipzig: Springer Berlin Heidelberg New York;
2007:501-521.
21. Internal Clinical Guidelines t. National Institute for Health and Care Excellence: Clinical
Guidelines. Diabetic Foot Problems: Prevention and Management. London: National Institute
for Health and Care Excellence (UK)
Copyright (c) 2015 National Institute for Health and Care Excellence.; 2015.
22. Crawford F, Cezard G, Chappell FM, et al. A systematic review and individual patient
data meta-analysis of prognostic factors for foot ulceration in people with diabetes: the
international research collaboration for the prediction of diabetic foot ulcerations (PODUS).
Health Technology Assessment. 2015;19:1-+.
23. Andersen H. Motor dysfunction in diabetes. Diabetes-Metabolism Research and Reviews.
2012;28:89-92.
24. Rogers LC, Frykberg RG, Armstrong DG, et al. The Charcot Foot in Diabetes. Diabetes
Care. 2011;34:2123-2129.
25. Jeffcoate WJ, Game F, Cavanagh PR. The role of proinflammatory cytokines in the cause
of neuropathic osteoarthropathy (acute Charcot foot) in diabetes. Lancet. 2005;366:2058-2061.
12
26. Alexiadou K, Doupis J. Management of diabetic foot ulcers. Diabetes Ther. 2012;3:4.
27. Peripheral Arterial Disease in People With Diabetes. Diabetes Care. 2003;26:3333-3341.
28. Elgzyri T, Larsson J, Thorne J, Eriksson KF, Apelqvist J. Outcome of Ischemic Foot
Ulcer in Diabetic Patients Who Had no Invasive Vascular Intervention. European Journal of
Vascular and Endovascular Surgery. 2013;46:110-117.
29. Prompers L, Schaper N, Apelqvist J, et al. Prediction of outcome in individuals with
diabetic foot ulcers: focus on the differences between individuals with and without peripheral
arterial disease. The EURODIALE Study. Diabetologia. 2008;51:747-755.
30. Prompers L, Huijberts M, Apelqvist J, et al. High prevalence of ischaemia, infection and
serious comorbidity in patients with diabetic foot disease in Europe. Baseline results from the
Eurodiale study. Diabetologia. 2007;50:18-25.
31. Boyko EJ, Ahroni JH, Davignon D, Stensel V, Prigeon RL, Smith DG. Diagnostic utility
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Amputation and Death, but Not Healing, in People With Diabetes Presenting With Foot Ulcers:
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70. Ragnarson Tennvall GA, J. Health-related quality of life in patients with diabetes mellitus
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17
Chapter 2. Systematic Review of Foot Problems and Health-related Quality
of Life of People with Diabetes
2.1. Introduction
The World Health Organization (WHO) defines health as “a state of complete physical, mental
and social well-being and not merely the absence of disease or infirmity”1. Measurements on
clinical data, morbidity and mortality are not capable of expressing all those dimensions on
health. Health-related quality of life (HRQOL) measures, though, are multi-dimensional and take
a person’s subjective perspective of their well-being through different health domains including,
but not limited to, physical, mental and social functioning.
Patients with diabetes have generally rated their quality of life lower than the general population,
but higher compared to people with other chronic diseases. However, when diabetes is associated
with other comorbidities, there is a significant decrement on quality of life2. A review on the EQ-
5D conducted by Janssen et al. showed that diabetic subjects with no complications had a utility
score of 0.76 (0.68, 0.83) while patients with microvascular and macro vascular complications
had 0.73 (0.57–0.89) and 0.73 (0.57–0.88), respectively3. Some studies have also shown that
diabetic individuals with foot ulcer have even lower HRQOL scores than the general diabetic
population, particularly in the mobility domain that may then impact other domains such as daily
activities, emotional and social functioning4-6
. Two literature reviews also reported that
ulceration and amputation decreases quality of life due to limitations on physical functioning4, 7
.
Individuals with diabetes are at constant risk of developing foot ulcers that if not treated lead to
longer treatment, depression and in more seriuous cases to lost of lower limbs. In fact, diabetes
has been the leading cause of non-traumatic amputations in Canada for years, even though most
of them are considered preventable. This shows the need for improvement of health-care towards
patients with diabetes at risk of foot problems and implementation of new interventions. Foot
problems in diabetes, however, are complex and range in symptomatology and clinical diagnosis,
which in turn reflect in different care and needs. Current clinical measurements are not able to
capture these nuances and HRQOL measures play an important role in assessing different health
domains and taking the patients’perspective into consideration for improving the quality of care.
18
The systematic review by Hoggs et al. (2012) examined the impact of foot diseases on diabetic
patients as a secondary objective8. His main objective was to assess the reliability and validity of
HRQOL instruments on diabetic foot diseases. The review searched for studies published until
2011 and the authors did not conclude whether there is a causal relationship or association
between diabetic foot conditions and HRQOL8.
Most studies reported on those reviews were cross-sectional and presented an association
between foot problems and HRQOL. However, due to the nature of the design of these studies,
authors could not conclude a causal relationship between the condition and HRQOL4, 7, 8
.
The current reviews on HRQOL in patients with diabetic foot problems did not conduct a meta-
analysis and were unclear as to whether they followed guidelines on the selection, extraction and
quality assessment. With this limitations in mind and the increase of studies on HRQOL, it is
important to conduct a comprehensive review conforming with the guidelines.
The aim of this study was to conduct a systematic review to assess the association of diabetic
foot problems and HRQOL.
2.2. Methods
The study protocol was developed before conducting the systematic review and it followed the
Preferred Reporting Items for Systematic Review and Meta-analysis Protocols (Prisma-P)9.
Conducting and reporting this review followed the Cochane and Preferred Reporting Items for
Systematic Reviews and Meta-analysis (PRISMA) guidelines10, 11
. The protocol was registered at
the Prospero database (CRD42015024748), an international database managed by CDR for
registering protocols of systematic reviews.
2.2.1. Eligibility criteria
Studies were included if they examined the relationship between diabetic foot problems,
including amputation, and HRQOL.
Studies were selected according to the following inclusion criteria, based on the PCOS
framework:
19
- Population: Adults (over 18 years old) medically diagnosed with type 1 or 2 diabetes and
presenting one of the following medically diagnosed foot problems: distal symmetrical
neuropathy with confirmed signs of sensory loss, peripheral vascular disease, foot ulcer,
Charcot foot and/ or amputation.
- Comparator: adults medically diagnosed with type 1 or 2 diabetes without the previously
mentioned foot problems, or with a different foot complication than the case group.
- Outcome: HRQOL was measured with a previously validated self-administrative
instrument.
- Studies: observational (cohort, case-control and cross-sectional studies) and experimental
studies published in scientific journals until July 2015, either in English, Spanish or
Portuguese.
Distal symmetrical neuropathy in diabetes is a complex disease and it can range from painful
symptoms to numbness with or without loss of sensation in the toes or foot12, 13
. In this review,
we were interested in investigating neuropathy as one of the main risk factors for diabetic foot
ulcer and one of the first stages of diabetic foot complications. Therefore, we included only
studies with confirmed diagnosis of loss of sensation and excluded studies that defined
neuropathy based on presence of pain, exclusively.
Studies were excluded if: (1) they were case-series, case-reports and editorials; (2) they
qualitatively measured health-related quality of life (i.e: interviews and group assessments); (3)
the HRQOL was measured using a proxy (i.e. physicians, caregivers or relatives) and it was not
self-assessed; (4) studies in which the objective was to analyze the psychometric properties of
HRQOL measures; (5) studies that used self-report measures on diabetes and foot problem
diagnosis as those are prone to information bias; (6) studies that reported magnitude, duration
and frequency of pain without associating its impact on quality of life.
2.2.2. Search Strategy
We accessed the following databases until July/2015: Medline (via Pubmed), Embase, CINAHL,
PsycInfo, Scopus and Web of Science. The search strategy was developed with the assistance of
a librarian. It included a combination of keywords, their synonyms and controlled vocabulary (i.e.
20
Mesh terms) such as “diabetic foot”, “foot ulcer”, “foot complications”, “quality of life”, “SF-
36”, “EQ-5D” (Figure 2.1). The references of included studies were also searched for further
studies.
2.2.3. Selection Process, Data Extraction and Quality Assessment
Two reviewers independently screened the titles and abstracts. Both reviewers retrieved and
assessed the full-text articles for inclusion and exclusion according to the eligibility criteria. In
case of any discrepancies between reviewers, a third party was consulted. The references of
included studies were assessed for additional material. Kappa statistics was calculated to
Figure 2.1. Search strategy used on Embase. Similar search strategy was used on all databases
1. exp diabetic foot/
2. exp diabetic neuropathy/
3. exp foot ulcer/ or ((foot or feet) and ulcer*).mp. [mp=title, abstract, heading word, table of contents, key concepts,
original title, tests & measures]
4. exp foot disease/
5. exp gangrene/
6. exp osteomyelitis/
7. exp leg amputation/
8. foot amputation/
9. ("foot complication" or "foot problem" or "foot infection" or necrosis).sh.
10. ("charcot foot" or "charcot arthropathy" or "charcot osteoarthropathy" or "neuro-osteoarthropathy" or "neuropatic
osteoarthropathy").sh.
11. peripheral occlusive artery disease/
12. exp peripheral vascular disease/
13. exp peripheral neuropathy/
14. ((foot or feet) and diabet*).mp. [mp=title, abstract, heading word, table of contents, key concepts, original title, tests &
measures]
15. exp foot/
16. exp diabetes mellitus/
17. 15 and 16
18. 1 or 2
19. diabet*.mp. [mp=title, abstract, heading word, table of contents, key concepts, original title, tests & measures]
20. 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13
21. 19 and 20
22. 14 or 17 or 18 or 21
23. exp "quality of life"/
24. exp wellbeing/
25. exp quality adjusted life year/
26. ("health-related quality of life" or qol or hrql or hrqol or qaly or "health status" or "patient report outcome").sh.
27. (assess* or evaluat* or tool or instrument or scale or measure* or index or battery or questionnaire or "self-report" or
"self-administration" or "survey").mp. [mp=title, abstract, heading word, table of contents, key concepts, original title, tests
& measures]
28. 26 and 27
29. short form 36/
30. exp Short Form 12/
31. ("EQ-5d" or "euroqol" or "SF-6d" or "short form" or DFS or "diabetic foot ulcer scale" or "rand-36" or norfolk or
neuroqol or "cardiff wound impact schedule" or CWIS).sh.
32. 29 or 30 or 31
33. 22 and 28
34. 22 and 32
35. 33 or 34
21
measure the agreement between reviewers and the agreement was considered fair, good and
excellent if kappa was between 0.40 and 0.59, 0.60 and 0.74, and 0.75 or over, respectively14
.
One reviewer extracted the data from included studies using an extraction form and the second
reviewer checked entries. The standardized form included information on general characteristics
of the study (design, setting, sample size), description of HRQOL measures, and characteristics
of participants.
Two reviewers independently appraised the quality of included studies using the “Quality
Assessment Tool For Quantitative Studies” created by the Effective Public Health Practice
Project (EPHPP)15
. Both reviewers discussed their evaluation and resolved any discrepancies
consulting a third party. The software EndNote (www.myendnoteweb.com) was used to store
and manage all references found from the previously mentioned databases.
2.2.4. Meta-analysis
We conducted a meta-analysis with HRQOL measures as continuous outcomes using
standardized mean difference (SMD) as the measure of effect. SMD was calculated for each
outcome measure as the mean difference divided by the pooled standard deviation. Furthermore,
we considered 0.2 as a small, 0.5 as a moderate and 0.8 as a large effect size16
. We performed the
random-effect model as described by the DerSimonian and Laird method to calculate the
summary statistics and considered a p-value<0.05 for statistical significance17
. To investigate
heterogeineity of results, chi-squared test and I2 statistics were calculated. We considered
presence of significant heterogeineity across studies when I2
was equal or greater than 50%,
coupled with Chi-squared test p-value achieving statistical significance (p<0.10)11, 18
.
We chose to pool only outcome of same HRQOL instrument to facilitate interpretation of results
and because each measure may have different structures and scoring system. We hypothesized
that even measures with similar content would create great heterogeinity and inconsistence in the
summary stiatistics.
The software Review Manager (Revman), version 5.3 (The Nordic Cochrane Centre, The
Cochrane Collaboration, 2014) was used to conduct the meta-analysis.
22
2.3. Results
The literature search identified 5,921 studies and 298 of them were included for full-text review.
After examination, 22 papers describing 21 studies were included in this systematic review with
9 of them included for quantitative synthesis. The agreement between reviewers resulted in a
kappa of 0.52 which is considered fair. The main reason for exclusion of studies were: no
analysis of the association between foot problems and HRQOL measures and no reports on
HRQOL measurements (Figure 2.2).
Figure 2.2. PRISMA flowchart of the systematic review search
RecordsidentifiedonMedline,Embase,
PsycInfo,ScopusandWebofScience(n=5,921)
Studieseligibleforscreening(n=3,469)
Duplicatesremoved(n=2,452)
Full-textarticlesassessedforeligibility(n=298)
Studiesexcluded(n=3,178)
Full-textarticlesexcludedfromthereview
(n=277):- Noanalysisoftherelationshipand
impactofdiabeticfootproblemson
HRQL(n=165)- NoHRQLmeasurements(n=28)
- Wrongpatientpopulation(n=33)- Diabetesand/orfootproblemsnot
medicallydiagnosedorspecified
(n=19)- Qualitativeoutcomemeasuresornot
self-administered(n=14)- Studynotpublishedinscientific
journal(n=6)
- Differentlanguage(n=3)- HRQLmeasurewasnotpreviously
validated(n=7)Studiesincludedinthisreview(n=21):
- Papersincludedinthisreview(n=22)
Studiesontype1 diabetes(n=2) Studiesontype2diabetes(n=4) Studiesontype1 and2 diabetes(n=15)
References,relatedarticles(n=1)
23
Table 2.1. Characteristics of included studies
Reference Study design Population, sample n, (%male), mean diabetes
duration (sd)
Diabetic foot problem criteria, sample n (%) HRQL instrument Overall
quality
Diabetes type 1
Lloyd, 199235 Cross-sectional Individuals with diabetes type 1 with a
duration of over 25 years and registered at the
Children's Hospital of Pittsburgh (USA);
N = 175 (50.3);
Diabetes duration = NR (NR)
DPN defined as patients with at least two
criteria symptoms, decrease or absence of
tendon reflexes, signs of sensory loss (light
touch, pinprick, and vibration perception
examination);
n= 102 (58.3);
DQOL: diabetes
specific instrument
Moderate
Trento, 201330 Cross-sectional Individuals with diabetes type 1 in the
diabetes registry of Turin (Italy);
N= 310 (53.5);
Diabetes duration = 17.3 (6.3)
DPN was assessed through medical tests,
though there are no details of type of tests;
n= 34 (11.0)
DQOL: diabetes
specific instrument
Weak
Diabetes type 2
Altenburg, 201119 Cross-sectional Individuals with type 2 diabetes visiting an
university clinic in Dresden (Germany);
N=94 (74.5);
Diabetes duration= 17 (NR)
Medical assessment for the presence of
ulcers;
n= 47 (50.0)
SF-12: generic
instrument (health
profile)
NeuroQoL: disease-
specific instrument
Moderate
Clarke, 200220 Cross-sectional Individuals newly diagnosed with type 2
diabetes participating in the UKPDS study in
the United Kingdom;
N= 3,192 (NR);
Diabetes duration= 10.6 (2.8)
Medical assessment for the occurance of
amputation;
n= 19 (0.6)
EQ-5D-3L and VAS:
generic instrument
(preference-based)
Moderate
Ijzerman, 201224 Cross-sectional Individuals with type 2 diabetes over 50 years
attending one of the 5 listed hospitals at
Netherlands;
N= 156 (73.7);
Diabetes duration = NR (NR)
DPN was diagnosed with the standard
clinical neurological examination. A cut off
of 5 was used to indicate presence of DPN;
n= 98 (62.8)
SF-36: generic
instrument (health
profile)
Weak
Wexler, 200637 Cross-sectional Individuals with type 2 diabetes attending one
of the two outpatient clinics listed in the study
located in Boston (USA);
N= 909 (51.1);
Diabetes duration= NR (NR)
PVD was assessed through medical records
and billing claims;
n= 130 (14.3)
HUI-3: generic
instrument
(preference-based)
Weak
Diabetes type 1 and 2
Lewko, 200726 Cross-sectional Individuals with well controlled diabetes type
1 or type 2 attending the medical centre at the
university of Bialystok (Poland);
N= 59 (35.6);
Diabetes duration:
Without DPN = 13.0 (9.3);
With DPN = 16.6 (11.3)
No mention on what tests were used to
diagnose neuropathy;
n= 22 (37.3)
SF-36: generic
instrument (health
profile)
Weak
24
Van Acker, 200932 Cross-sectional Individuals with a diagnosis of diabetes type 1
or 2 of more than one year attending one of
the 40 outpatient clinics across Belgium;
N= 1,111 (56.0);
Diabetes duration:
Type 1: 16.5 (NR);
Type 2: 11.0 (NR)
DPN was considered present if patients did
not feel the stimulus on more than one of the
tested sites in the monofilament test or if the
pinprick stimulus was not felt in at least one
foot. The diagnosis of painful neuropathy
was based on the presence of neuropathy and
a DN4 score higher than 4;
n= 478 (43.0)
SF-12: generic
instrument (health
profile)
Moderate
Ali Alzhrani,
201134
Cross-sectional Individuals with type 1 or 2 diabetes attending
King Abdelaziz university (Saudi Arabia);
N=180 (64.4);
Diabetes duration:
Without foot ulcer = 11.1 (1.0)
With foot ulcer = 15.9 (1.3)
Foot ulcer was assessed through medical
records;
n= 60 (33.3)
SF-36: generic
instrument (health
profile)
Moderate
García-Morales,
201122
Cross-sectional Individuals with type 1 or 2 diabetes attending
one of two centres in Madrid (Spain);
N= 421 (58.9);
Diabetes duration:
Without foot ulcer = 14.6 (10.9);
With foot ulcer = 15.8 (10.8)
Foot ulcer were considered present after a
medical diagnosis confirmed an ulcer
located bellow the malleoli;
n= 163 (38.7)
SF-36: generic
instrument (health
profile)
Weak
Ragnarson
Tennvall, 200028
Cross-sectional Individuals with type 1 or 2 diabetes treated
for foot ulcer at Lund university hospital
(Sweden);
N= 130 (65.5);
Diabetes duration= 19 (NR)
Medical records were assessed for the
presence of ulcer and amputation;
diabetic foot:
foot ulcer: 56 (43.1);
minor amputation: 52 (40.0);
major amputation: 26 (20.0)
EQ-5D-3L and VAS:
generic instrument
(preference-based)
Weak
Raspovic, 201439 Cross-sectional Individuals with type 1 or 2 diabetes
hospitalized with a diabetic foot infection at
an university hospital and diabetic people who
volunteered without any foot problems in the
United States;
N= 86 (79.1);
Diabetes duration:
Without foot ulcer = 9.2 (8.3)
With foot ulcer = 15.0 (9.6)
Medical assessment for the presence of
diabetic foot ulcers and infection;
n= 43 (50.0)
SF-36: generic
instrument (health
profile)
FAAM: disease-
specific instrument
Weak
Sanjari, 201136 Cross-sectional Individuals with type 1 or 2 diabetes attending
one of the four clinics in Kerman (Iran);
N= 132 (62.1);
Diabetes duration:
Without foot ulcer = 10.4 (6.7);
With foot ulcer= 11.6 (7.6)
Medical assessment for the presence of
diabetic foot ulcers;
n= 54 (40.9)
SF-36: generic
instrument (health
profile)
Weak
Valensi, 200531 Cross-sectional Individuals with type 1 or type 2 diabetes who
visited one of the 98 clinicians registered in
France;
Medical assessment for the presence of
diabetic foot ulcers;
n= 239 (67.3)
SF-36: generic
instrument (health
profile)
Weak
25
N= 355 (60.8)
Diabetes duration:
Without foot ulcer = 12.6 (8.6);
With foot ulcer = 17.3 (11.1)
DFU: disease-
specific instrument
Davies, 200021 Cohort study Individuals with a diagnosis of diabetes type 1
or 2 attending diabetic clinics in southeast
Wales (UK);
N=280 (NR);
Diabetes duration= NR (NR)
Medical assessment of neuropathy through
the absence of vibration, foot ulcer and
amputation;
DPN= 150 (53.6);
foot ulcer= 20 (7.1);
amputation= 10 (3.6)
SF-36: generic
instrument (health
profile)
Weak
Happich, 200823 Cohort study Individuals with type 1 or 2 diabetes
diagnosed on or before January 2002 and
treated for DPN in 2002 in Germany;
N= 185 (58.9);
Diabetes duration= 15 (NR)
Medical records were assessed for the
presence of neuropathy with and without
symptoms, foot ulcer and amputation;
DPN without symptoms = 35 (18.9);
DPN with symptoms= 47 (25.4);
foot ulcer= 47 (17.3);
amputation= 71 (38.4)
SF-12: generic
instrument (health
profile)
Norfolk-QoL:
disease-specific
instrument
Moderate
Ikem, 200938 Cross-sectional Individuals with type 1 or 2 diabetes with a
diabetic foot ulcer or DPN and without history
of amputation and peripheral vascular disease
attending an univeristy hospital in Nigeria;
N= 39 (64.1);
Diabetes duration= 7.4 (8.0)
Assessment of presence of ulcer. DPN was
defined as patients who scored higher than 3
at the neuropathy disability score;
foot ulcer= 21 (53.8);
DPN= 18 (46.1)
WHO-BREF:
generic instrument
(health profile)
Weak
Ribu, 200829
Jelsness-Jorgensen,
201125
Cohort study Individuals with diabetes type 1 or 2 attending
outpatient clinics in Norway;
N= 257 (66.5);
Diabetes duration:
Without foot ulcer = 15.5 (12.2);
With foot ulcer = 19.0 (13.0)
Clinical assessment for the presence of an
ulcer on or bellow the malleolus;
n= 127 (49.4)
SF-36: generic
instrument (health
profile)
Moderate
Nabuurs-Franssen,
200527
Cohort study Patients with type 1 or 2 diabetes with an
unhealed ulcer for at least 4 weeks in one of
the 81 centres in the US and Europe;
N= 454 (NR);
Diabetes duration= NR (NR)
Clinical evalution for the presence, duration
and size of foot ulcer;
persistent ulcer= 132 (29.1);
healed ulcer= 162 (35.7)
SF-36: generic
instrument (health
profile)
Moderate
Winkley. 200933 Cohort study Diabetic patients with type 1 or 2 with their
first ulcer presenting at hospitals foot and
community chiropody clinics in four health
authorities in South London;
N= 241 (64.3);
Diabetes duration= 14.7 (13.3)
Diabetic foot ulcer were defined as an ulcer
in the anatomical foot, with a full-thickness
break in the epithelium with a minimum
width of 5mm
SF-36: generic
instrument (health
profile)
Moderate
NR: not reported
26
2.3.1. Description and Quality Assessment of Included Studies
The majority (67%) of studies were conducted in Europe19-33
and were funded by health research
institutes20, 21, 24, 25, 28, 29, 34-37
(43%)(Table 2.1). The overall quality of studies was week to moderate
(Table 2.1). Given that majority (67%) of studies were cross-sectional19, 22, 24, 26, 28, 30-32, 34-39
they
would be considered as a weak design for inference of causality. In addition, most studies
controlled for age, gender and diabetes duration as confounding variables, but lack measurement or
control for other possible confounders such as comorbidities, economic and smoking status21-25, 27-29,
31, 37, 39, 40. As a result, the majority were also considered weak for control of confounders.
2.3.2. Participants
The included sample sizes varied from 59 to 6,251 and the number of participants with foot
problems ranged from 19 to 239. Most studies were on patients with diabetic foot ulcers, followed
by subjects with diabetic peripheral neuropathy. 19% of studies included amputees and only one
study was on patients with Charcot foot and another one studying the association of peripheral
vascular disease and HRQOL (Table 2.1).
Figure 2 shows that only 2 studies30, 35
were on type 1 diabetes with the mean age ranging from 32.8
to 37.3, while 4 studies19, 20, 24, 37
were on exclusively on type 2 diabetes patients and these patients
were older as their mean age ranged from 62 to 68 years old. 15 studies21-23, 25-29, 31-34, 36, 38-40
were
on both type of diabetes with majority of participants diagnosed with type 2 diabetes and with mean
age varying from 46 to 68 years old (Table 2.1).
2.3.3. Health-related Quality of Life
The methods to assess HRQOL varied and 10 different instruments were used in the 21 included
studies. All studies, apart from two, applied a generic instrument and the most common measures
were: the SF-36 (n=11), followed by the SF-12 with 3 studies and the EQ-5D-3L with 2 studies
(Table 2.1). A total of five specific HRQOL instruments were used: three were specific to diabetic
foot problems (DFU31
, Norfolk-QoL23
, NeuroQol19
), one was specific to foot problems (FAAM39,
40) and one was a diabetic specific measure (DQOL
30, 35) (Table 2.1).
27
Two studies30, 35
with subjects with type 1 diabetes that assessed the association and impact of
neuropathy in HRQOL measured with the diabetes quality of life instrument (DQOL). Both studies
did not find significant differences on the overall DQOL score between patients with and without
neuropathy after controlling for confounding variables30, 35
. Trento et al30
also did not find any
differences for each of the four domains of DQOL.
Welxler et al found that type 2 diabetes participants with peripheral vascular disease had lower
HRQOL compared to those without the vascular disease37
. However, the results were based on
simple descriptive statistics prone to confounding variables.
Studies on neuropathy with type 2 or both types of diabetes used different diagnostic tools and
criteria for defining the presence of this foot problem. The majority of these studies found no
statistical difference between patients with and without neuropathy on physical and mental health24,
26, 32. Van Acker et al
32 and Happich et al
23 found that while asymptomatic patients had no
differences in the physical and mental scores of SF-12, patients with neuropathic symptoms had
significant decrements in both domains. Happich et al also reported worse health in symptomatic
neuropathy measured through a disease speficic instrument23
.
The progression of neuropathy can lead to the diabetic Charcot foot, which, according to Raspovic
and Wukich,40
had lower scores on physical functioning, physical role, bodily pain, general health,
vitality, social functioning and role emotional. Measures on physical health were lower for patients
with Charcot foot, but there were no differences between both groups on mental health40
.
The majority of cross-sectional studies reported that participants with diabetic foot ulcer had lower
social, emotional, mental and physical health when compared to those without them and the general
diabetic population22, 25, 31, 34, 38, 39
. In addition, the number, duration and severity of ulcers were
correlated with lower physical, social, emotional, vitality domains and general health31
. One study
found that diabetic foot ulcer was correlated with lower HRQOL, but it was statistically significant
only on the physical functioning domain (p<0.001)36
. However, it is important to note that the
control group (i.e. patients without diabetic foot ulcer) in this Iranian study had low scores in all SF-
36 domains compared to control groups of other studies36
.
Three studies assessed longitudinal data, assessing changes in SF-36 of patients with diabetic foot
ulcer for periods varying from 8 to 18 months27, 29, 33
. Winkley et al33
reported that patients who had
a recurrence of foot ulcer, an amputation or unhealed ulcer after 18 months had significantly lower
28
mental health than patients who healed but no statistically significant differences were found in
their physical health. However, Nabuurs-Franssen et al27
and Ribu et al29
found that at the end of
follow up patients with healed ulcer had better HRQOL than those with persistent ulcer, mainly in
the social functioning, emotional and physical domains. While Nabuurs-Franssen et al27
reports that
healed patients improved the previously mentioned health domains and patients with persistent
ulcer deteriorated, Ribu et al29
found that only social functioning changed significantly through time
for both groups and patients with persistent ulcer also reported deterioration of mental health over
the period.
Studies on patients with an amputation reported significant decrements on utility scores measured
by the EQ-5D20, 28
. Clarke reported that amputation reduced the utility score by 0.280 (95%CI: -
0.389, -0.170, p<0.001) and had greater impact than other comorbidities such as stroke and
myocardial infarction20
, while Ragnarson-Tenvall showed that a major amputation decreased the
index score by 0.257 (p=0.001)20, 28
. However, both studies had a very small sample of amputees.
Only three studies compared different stages of foot disease (neuropathy, foot ulcer and amputation)
in the same population21, 23, 28
. One study described lower utility scores between groups with ulcer
and minor amputation, both with better perceived health compared to the group with major
amputation28
. Davies, comparing foot complications, found the largest decrement in physical
summary score in patients with an amputation followed by those with neuropathy, but little
differences in this score were found for individuals with an ulcer21
. The study also reported that
patients treating for ulcer had the largest decrement in mental summary score, while those with an
amputation were not different in this domain from patients with no foot complication21
. Differently,
Happich reported similar decrements on physical and mental summary score associated with ulcer
and amputation23
.
2.3.4. Meta-analysis
We conducted a meta-analysis with the 8 health domains and summary scores of the SF-36 and SF-
12 as the outcome measures. Studies were included if they presented both scores and standard
deviations. We excluded the study from Ali Alzahrani34
from the analysis as the scores were
calculated differently from the other studies.
29
Table 2.2 shows the results of the meta-analysis comparing patients diagnosed with diabetes and
with or without foot ulcer, in which heterogeneity ranged from 29 to 91%. All domains had
significant heterogeneity (p<0.10, I250%), apart from the mental component summary. Four
studies22, 29, 36, 39
were included for assessment of the health domains, while 5 studies were included
for analysis of summary scores19, 21, 29, 33, 39
. Small to medium effect size were found for vitality, role
emotional, mental health domains and mental component summary score, though mental health
domain did not achieve statistical significance. The other health domains had medium to large
effect size which were also statistically significant. Further details are found in Appendix A.
We also analyzed the differences between patients with diabetes with and without neuropathy and
found only statistical significance in the phycial functioning domain and physical component
summary score with small to medium effect size (Table 2.3). Only the role emotional domain
presented significant heterogeneity, although there were only two studies reporting the summary
scores21, 26
. Further details on our meta-analysis are described on Appendix A.
Table 2.2. Meta-analysis of SF-36 and SF-12 domains and summary scores comparing participants
with and without foot ulcer
Domain Number of studies Participants Heterogeneity.
I2 (%)
Effect estimate (SMD)
95% CI
Physical functioning 4 710 71 -0.94 [-1.28, -0.61]
Role physical 4 705 91 -0.94 [-1.54, -0.33]
Bodily pain 4 715 80 -0.54 [-0.92, -0.15]
General health 4 713 80 -0.58 [-0.97, -0.18]
Vitality 4 712 75 -0.47 [-0.82, -0.12]
Social functioning 4 715 70 -0.66 [-0.98, -0.34]
Role emotional 4 709 64 -0.36 [-0.65, -0.07]
Mental health 4 711 84 -0.42 [-0.84, 0.01]
Physical component summary 5 511 89 -0.68 [-1.30, -0.06]
Mental component summary 5 511 29 -0.28 [-0.51, -0.04]
30
Table 2.3. Meta-analysis of SF-36 and SF-12 domains and summary scores comparing participants
with and without peripheral neuropathy
Domain Number of studies Participants Heterogeneity.
I2 (%)
Effect estimate (SMD)
95% CI
Physical functioning 3 446 0 -0.25 [-0.45, -0.06]
Role physical 3 446 26 -0.11 [-0.35, 0.13]
Bodily pain 3 446 34 -0.14 [-0.40, 0.11]
General health 3 446 0 -0.16 [-0.35, 0.04]
Vitality 3 446 0 0.09 [-0.10, 0.29]
Social functioning 3 446 48 0.01 [-0.29, 0.30]
Role emotional 3 446 72 0.07 [-0.34, 0.48]
Mental health 3 446 0 0.10 [-0.09, 0.29]
Physical component summary 2 309 0 -0.39 [-0.62, -0.16]
Mental component summary 2 309 37 0.05 [-0.29, 0.39]
2.4. Discussion
This study attempted to investigate the current evidence of the impact foot problems have on
HRQOL of individuals diagnosed with diabetes.This systematic review included 21 studies, mostly
cross-sectional, of moderate to week methodological quality that is decreasing the generalizability
and accuracy of our results. We found that diabetic foot complications are associated with
impairment in HRQOL. While neuropathy was associated with lower physical functioning, patients
with ulcer, a more advanced stage, had significant decrements in social, physical and mental health.
Amputation was also associated with lower HRQOL, but it remains unclear, whether this condition
leads to larger decrements in health domains than diabetic foot ulcers.
There was a lack of population-based studies as most studies were performed within hospitals and
outpatient clinics. We also found that most studies included both types of diabetes with majority of
patients being type 2. Therefore, most of our findings are more of a reflection on HRQOL in foot
problems of type 2 diabetes.
There were only two studies30, 35
with type 1 diabetic population included in our review and both
found no decrements in quality of life on patients with neuropathy compared with non-neuropathy
patients. A possible reason for the lack of studies on type 1 diabetes is the much lower prevalence
of type 1 compared to type 2 diabetes. Both included studies30, 35
varied in settings, duration of
disease and analysis approach that call for caution while interpreting the results.
31
An earlier systematic review by Hogg et al analyzed the impact of foot conditions on HRQOL as a
secondary objective8. They determined that the advancing stages of foot problems were correlated
with decrements on quality of life, though caution on generalizability was required, mainly in
patients with amputation8. Compared to Hogg’s work
8, our systematic review included fewer
studies as some studies included in their work did not meet our inclusion criteria. Similarly, through
meta-analysis, we found that neuropathy had only small and not statistically significant effect size,
whereas ulceration, a more advanced stage of diabetic foot, had a significant medium to large effect
on most domains of HRQOL measured with a generic instrument. Our review also pointed to an
association of lower HRQOL with amputation, but it was unclear whether this condition was
different from ulceration in terms of quality of life. The studies with a group of amputees were
small in sample size and had a lack of control for confounding variables. The only prospective
cohort33
following patients with diabetic foot ulcer who underwent amputation found no additional
decrement on physical and mental health, though the sample size was small (26 out of 241 patients).
We found a lack of studies exlusively on diabetic patients with peripheral vascular disease and
Charcot foot with the included studies prone to confounding variables and weak study design.
Consequently this is limiting the validity of correlation between diabetic foot disease and lower
HRQOL in our study. An explanation for lack of HRQOL measurements on peripheral vascular
disease is that some diabetes studies, in order to improve statistical power at the costs of loosing
information, categorize peripheral vascular disease with other comorbidities or as a macrovascular
complication along with stroke and coronary artery disease.
We found that majority of investigators prefer the use of generic HRQOL measures such as the SF-
36 compared to disease specific measures. The advantage is that it allows for comparison with other
diabetic complications as well as other chronic conditions. The issue is that these measures may not
be sensitive or responsive to specific issues of diabetes and diabetic foot conditions. Therefore, the
lack of significance on some health domains of these foot conditions do not necessarily mean these
conditions do not have an impact on HRQOL measurements. For that reason, it is advisable to use a
specific and a generic HRQOL instrument in studies comparing diabetes complications. We also
found that some authors did not describe how scores were calculated. Further, two studies
calculated an overall score for the SF-36, even though the guidelines for this tool do not advise this
approach22, 36
.
32
The strength of this study were the performance of search in different databases with assistance of a
librarian and conduction of every step following the PRISMA and Chocrane handbook guidelines.
Another strength was the performance of a meta-analysis, a quantitative analysis, showing the effect
size of ulceration and neuropathy in different health domains. The use of standardized mean
difference (SMD) has the advantage of easy calculation and interpretation. The disadvantage of this
type of estimate is that it lacks accountability for differences between participants and variation of
standard deviation. Some authors have suggested alternatives to SMD by using minimal important
difference (MID) to standardized the mean differences, instead of the standard deviation41, 42
.
One criticism of our review is that we excluded studies that based on the self-report foot diagnosis.
A result of that is the exclusion of some population-based studies with a larger sample size. On the
other hand, these studies are more likely prone to information bias43, 44
, specially because
neuropathy and peripheral vascular disease can be asymptomatic. Another criticism is that we
pooled participants independently of their diabetes type. Participants with type 1 and type 2 diabetes
will have different experiences through life and perspective on their health, as the former type
usually apperas in childhood and the later is associated with other comorbidities. However, Van
Acker et al32
reported no significant difference between participants with type 1 and 2 on the impact
of neuropathy in HRQOL. It was our initial intention to run sub-analysis based on the type of
diabetes, but the lack of studies with type 1 participants while majority included both types impeded
that.
The nature of our research question limits us to observational studies that are at higher risk of bias
and confounding variables. Most included studies controlled for age, gender, diabetes duration and
HbA1c. However, we found that some studies did not mention any control for confounding
variables and lack of measurement of diabetic complications that could influence results. The lack
of studies with higher methodological quality, prospective design with longer follow up, larger
sample size of participants with amputation, peripheral vascular disease, Charcot foot within the
same population limits the validity of the association and magnitude foot conditions have on
HRQOL.
There are also methodological limitations in this systematic review. First, we limited to studies
published in three different languages and into scientific journals. Consequently, there is a
possibility of publication bias as we did not search the grey literature. Second, we did not attempt to
33
contact authors of included studies to improve the quality of information. Third, the authors of this
review were not blinded to information of the included studies as our resources were limited.
Finally, one criticism was the performance of meta-analysis even with the presence of high
heterogeneity.
2.5. Conclusion
Studies have shown that diabetic foot complications are associated with decreased HRQOL and the
severity of the condition correlates with lower HRQOL. However, there were few studies conducted
with disease-specific instruments and comparing the different stages of diabetic foot diseases in a
population-based sample.
Future cohort studies following diabetic patients and the changes of HRQOL over the evolution of
the foot satus would be needed to further strenthening our findings as well as providing information
from the causal relationship between them. This would improve our knowledge on the health status
of these patients and what health domains could be the target in interventions leading to better well-
being of diabetic population.
34
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39
Chapter 3. Health-related Quality of Life of Adults with Type 2 Diabetes
Reporting Foot Problems in Alberta
3.1. Introduction
The International Diabetes Federation estimates that 415 million people have been diagnosed with
diabetes in 2015 and the prevalence will rise to more than 642 million cases by 20401. Type 2
diabetes represents the majority of these cases up to 91% in high-income countries2, 3
. About 2.8%
of all deaths in 2012 were attributed to diabetes, which ranked the condition as the 6th
leading cause
of mortality in Canada4. In addition, individuals with diabetes have reported lower health-related
quality of life (HRQOL) compared to the general population5. This is due to several complications
associated with diabetes such as vision impairment, renal diseases, cardiovascular problems and
diabetic foot problems including ulcers. In fact, diabetes is the leading cause of non-traumatic
amputations and 85% of them are caused by non-healing of diabetic foot ulcers6.
Distal symmetrical neuropathy and peripheral vascular disease (PVD) are two important risk factors
for the development of foot ulcers7, 8
. Both conditions cause patients to loose sensitivity and have
poor circulation in the lower extremities that can also delay healing time and lead to amputations7-9
.
Two literature reviews have shown that diabetic foot ulcers and amputations have a negative effect
on HRQOL, especially in the physical health domain. However, studies were unclear on the impact
foot problems have on mental health as they differ in clinical settings, definition of foot problems,
and used HRQOL instruments10, 11
. There is lack of evidence on the extent neuropathy and
peripheral vascular disease affect HRQOL in diabetes12
. In addition, there are no reports on
HRQOL of the diabetic population with foot problems living in Alberta, Canada. It is important to
assess HRQOL in the provincial level because these measurements are affected by culture and
ethnicity background. Such information may also assist health-care professionals to make
appropriate interventions targeting the affected health domains. The aims of this study, was to
assess and compare the HRQOL between people with type 2 diabetes with and without foot
problems (neuropathy, PVD, ulcer and amputation) living in Alberta.
40
3.2. Methods
3.2.1. Study Population
The data were obtained from the Alberta's Caring for Diabetes (ABCD) cohort study, an ongoing
prospective observational study funded by Alberta Health. The overall aims of the ABCD study are
to better understand the factors affecting care and outcomes in patients with type 2 diabetes in
Alberta. The study included 2040 individuals over 18 years of age with type 2 diabetes, who could
communicate in English and signed the consent form. The recruitment period was from December
2011 to December 2013. Further information on the design, rationale and baseline characteristics of
the ABCD study sample can be found elsewhere13, 14
.
3.2.2. Measures
A self-administered questionnaire was mailed to all participants who completed the informed
consent form. The survey included questions on socio-demographic, health, lifestyle and diabetes-
related variables, comorbidities, care management and health-related quality of life.
Additional questions on foot complications were also included in the survey. Participants were
asked to report if they have ever been diagnosed with any of the following foot problems:
neuropathy, peripheral vascular disease (PVD), ulcer/infection, and gangrene/amputation.
The survey also included questions on ever being diagnosed by a health care professional on the
presence of: obesity, respiratory problems, arthritis, thyroid problems, cancer, retinopathy, kidney
failure, heart disease and stroke. Presence of hypertension and dyslipidemia were based on self-
report of either a diagnosis by a health-care professional, or taking medications for these conditions.
3.2.3. Health-related Quality of Life
HRQOL was measured using two generic instruments: The Medical Outcome Study 12-item Short
Form Health Survey version 2 (SF-12 v.2) and the 5-level EuroQol 5-Dimension Questionnaire
(EQ-5D-5L)15, 16
.
The EQ-5D-5L is a preference-based measure comprised of 5 domains (mobility, self-care, usual
activities, pain/discomfort and anxiety/depression) with 5 possible levels of severity of problems: 1
41
“no”, 2 “mild”, 3 “moderate”, 4 “severe”, and 5 “extreme. The Canadian scoring algorithm was
used to calculate the index score, which has a possible range from -0.148 to 0.94917
. The instrument
also has the visual analogue scale (VAS): as an overall health rating scale, ranging from 0 (the
worst imaginable health) to 100 (the best imaginable health). However, this scale was not used in
the survey.
The SF-12v.2 is a short version of the commonly used SF-36 and measures 8 different health
domains: physical functioning (PF), role limitations due to physical problems (RP), bodily pain
(BP), general health (GH), energy and vitality (VT), social functioning (SF), role limitation due to
emotional problems (RE) and mental health (MH)15
. We calculated the raw scores ranging from 0 to
100 for each of the health domains, where higher scores indicate better health. Two summary scores,
the Physical Component Summary (PCS) and the Mental Component Summary (MCS), are derived
from these eight domains and are typically the focus of the SF-1218
. Based on the scoring system
described by Fleishman JA et al, we calculated the summary scores based on the US norm
population obtained from the Medical Expenditure Panel Survey (MEPS)18
.
Participants also completed the Short Form of the Problem Areas in Diabetes Scale (PAID-5), a
disease-specific instrument originally composed of 20 items measuring emotional and mental
distress related to diabetes. The short form contains 5 items and studies have shown reliability and
validity for use on type 2 diabetes19, 20
. The summary scale ranges from 0 to 20 with higher scores
indicating more diabetes-related distress19
.
3.2.4. Statistical Analysis
Descriptive statistics were used to verify the distribution and characteristics of the socio-
demographics, health status and HRQOL variables in the sample. Chi-square, Fisher’s exact, t-tests,
ANOVA and non-parametric tests were used to examine the differences in proportion and means
among groups as applicable. Mean imputation was used for missing values (<10% of the sample) in
continuous variables (age, PCS, MCS and EQ-5D index and PAID scores). The use of mean
imputation in these cases were considered not to produce bias results21
.
After carrying a univariate regression analyses, the variables that were statistically significant
and/or clinically important were included as independent variables in the multiple regression
42
models, where the HRQOL measures (PCS, MCS, EQ-5D index and PAID-5) were dependent
variables. Based on clinical pathways of ulceration and amputation8, 9
, we assumed that people with
neuropathy and PVD were high-risk groups, who could develop an ulcer/infection, which could
culminate into the development of an amputation. Accordingly, participants were grouped into the 6
following groups: no complications; only neuropathy; only PVD; neuropathy and PVD; ulcer, and
amputation regardless of concurrent presence of ulcer. In this analysis each individual was included
in only one of the foot disease categories above.
To account for the possible violation of homoscedasticity and distribution of error of the HRQOL
measures, we conducted a multiple linear regression combined with robust standard error, a method
that has shown to generate valid measures in large samples22
. Furthermore, we conducted a
generalized linear model with gamma distribution for EQ-5D index score. Since this different
approach had similar findings with the linear regression, we opted to not report those results here.
The statistical analysis was conducted with STATA 13 for Mac (www.stata.com); in all cases, a p-
value < 0.05 was considered for statistical significance.
3.2.5. Ethics
The study received ethical approval by the University of Alberta Health Research Ethics Board
(reference # Pro00016667).
3.3. Results
3.3.1. General Characteristics of Participants
Out of the 2040 included participants, 105 individuals were excluded from the analysis due to:
unknown gender (n=13) and HRQOL was measured with other measures (i.e., SF-12v.v1 and EQ-
5D-3L) (n=92). The participants excluded from the analysis were significantly more educated and
had lower emotional distress measured with PAID-5 than the included participants (Table 3.1).
The average age of the included sample was 64.5 (standard deviation (SD) 10.7) with average
diabetes duration of 12.6 (SD 10.0) years and average of 3.5 (SD 1.7) medical conditions. The most
common foot problem was PVD (29.2%) followed by neuropathy (19.2%) and ulcer (6.1%). Few
people had an amputation of limbs (1.4%) (Table 3.1).
43
Table 3.1. Socio-demographic and clinical characteristics of the included and excluded respondents
Characteristics Included sample (n=1,935) Excluded sample(n=105) p-value
Age - mean (SD) 64.5 (10.7) 61.9 (7.4) 0.13
Gender - n(%) 0.93
- Female 875 (45.2) 42 (45.6)
- Male 1,060 (54.8) 50 (54.4)
Marital Status - n(%) 0.79
- Married 1,379 (71.3) 80 (76.2)
- Not Married 556 (28.7) 25 (23.8)
Education - n(%) 0.001
- Less than high school 285 (14.7) 3 (2.9)
- High School or more 1,650 (85.2) 102 (97.1)
Ethnicity - n(%) 0.25
- Caucasian 1,752 (90.5) 100 (95.2)
- Aboriginal 46 (2.4) 2 (1.9)
- Others 137 (7.1) 3 (2.9)
Annual household income - n(%) 0.15
- <$80,000 1,481 (76.5) 74 (70.5)
- >=$80,000 454 (23.5) 31 (29.5)
Insulin use - n(%) 667 (34.5) NA
Foot problems
- Neuropathy - n(%) 371 (19.2) NA
- PVD - n(%) 564 (29.2) NA
- Ulcer - n(%) 118 (6.1) NA
- Amputation - n(%) 28 (1.4) NA
Number of medical conditions* - mean (SD) 3.5 (1.7) NA
- Dyslipidemia - n(%) 1,558 (80.5) NA
- Obesity - n(%) 1,093 (56.5) NA
- Respiratory problems - n(%) 368 (19.0) NA
- Arthritis - n(%) 952 (49.2) NA
- Thyroid Problem - n(%) 426 (22.0) NA
- Cancer - n(%) 262 (13.5) NA
- Retinopathy - n(%) 161 (8.3) NA
- Kidney Failure - n(%) 86 (4.4) NA
- Heart disease - n(%) 384 (19.8) NA
- Hypertension - n(%) 1,433 (74.1) NA
- Stroke - n(%) 135 (7.0) NA
Smoking - n(%) 0.58
- Never 793 (41.0) 43 (41.0)
- Current Smoker 199 (10.3) 14 (13.3)
- Quit smoking 943 (48.7) 48 (45.7)
PAID-5 - mean (SD) 4.3 (4.3) 3.3 (3.7) <0.01 p-value: included vs excluded sample; NA: not available; PAID-5: Short form of the Problem Area in Diabetes Scale; SD: standard
deviation
*The number of medical conditions was calculated excluding the diabetic foot problems and was based on the presence of the
following medical conditions: dyslipidemia, obesity, respiratory problems, arthritis, thyroid problem, cancer, retinopathy, kidney
failure, heart disease, hypertension and stroke
44
3.3.2. Health-related Quality of Life
The average PCS and MCS scores were 44.25 (10.33) and 47.87 (9.39), respectively. Individuals
with foot problems had lower scores in all 8 domains of SF-12 compared to their counterparts
without foot problems. Participants with PVD had lower scores in all domains than participants
with neuropathy, except for the bodily pain domain. As a result, the mental and physical summary
scores were lower in participants with PVD than neuropathy. Participants reporting neuropathy and
PVD had lower scores in all domains and summary scores of SF-12 compared to individuals who
reported just one of the conditions (Table 3.2).
The lowest scores of SF-12 were found between individuals reporting an amputation and foot ulcer,
with the later recording more problems in the bodily pain, social functioning, role emotional and
mental health domain. Nonetheless, the lowest physical and mental summary scores were found in
individuals reporting an amputation.
Table 3.2 also shows the distribution of response for each of the five dimensions of EQ-5D-5L. We
found a ceiling effect on the self-care domain and low number of individuals reporting severe
problems or inability in this domain. Few people with foot problems reported no pain and most
participants with ulcer reported moderate pain. Individuals reporting any foot condition also
described some level of problems with mobility, depression/ anxiety and moderate to severe
problems with usual activities. These individuals had lower EQ-5D index scores when compared to
the control group, with participants with ulcer having the lowest score.
The overall mean PAID-5 score of our sample was 4.34 (4.35). Higher distress was found in
participants with foot problems, in particular participants with ulcer followed by those with an
amputation (Table 3.2).
Table 3.2. Results of the SF-12v2 and proportion of response of the EQ-5D-5L
None
(n=1,214)
Neuropathy
(n=123) PVD (n=287)
Neuro & PVD
(n=186) Ulcer (n=97)
Amputation
(n=28)
SF-12v.02
PF - mean (SD)* 75.45 (30.31) 61.79 (35.26) 53.20 (34.04) 46.85 (34.87) 44.30 (32.43) 34.82 (36.85)
RP - mean (SD)* 73.39 (27.12) 63.67 (29.73) 56.03 (29.24) 48.95 (29.76) 44.98 (27.56) 33.93 (26.76)
BP - mean (SD)* 73.82 (28.40) 60. 79 (28.77) 61.66 (30.29) 53.47 (31.05) 48.81 (29.84) 49.11 (30.03)
GH - mean (SD)* 65.94 (21.50) 57.78 (23.26) 55.04 (23.65) 49.56 (25.76) 47.70 (25.95) 42.86 (26.58)
VT - mean (SD)* 56.97 (23.86) 51.02 (23.82) 48.34 (24.77) 43.08 (23.81) 43.59 (25.60) 41.97 (18.07)
45
SF - mean (SD)* 80.91 (25.52) 72.36 (29.99) 71.45 (28.17) 65.88 (30.27) 58.52 (31.02) 61.65 (29.27)
RE - mean (SD)* 81.89 (22.98) 74.80 (26.15) 72.12 (26.47) 71.42 (26.14) 65.39 (31.04) 66.96 (28.30)
MH - mean (SD)* 72.99 (20.07) 69.82 (20.92) 69.16 (20.01) 66.38 (21.02) 64.70 (21.39) 66.52 (21.53)
PCS - mean (SD)* 47.02 (9.22) 42.62 (10.55) 40.87 (9.97) 38.21 (10.46) 36.37 (9.74) 33.11 (9.78)
MCS - mean (SD)* 49.30 (9.00) 46.83 (9.93) 46.28 (8.90) 44.79 (9.68) 43.35 (10.20) 43.17 (9.52)
EQ-5D-5L
Mobility - %(n)*
No problem 58.90 (708) 32.79 (40) 31.34 (89) 21.20 (39) 16.49 (16) 10.71 (3)
Slight problem 23.13 (278) 37.70 (46) 29.93 (85) 23.91 (44) 20.62 (20) 21.43 (6)
Moderate problem 14.23 (171) 22.13 (27) 28.17 (80) 37.50 (69) 41.24 (40) 35.71 (10)
Severe problem 3.66 (44) 6.56 (8) 9.86 (28) 16.30 (30) 20.62 (20) 32.14 (9)
Unable to walk 0.08 (1) 0.82 (1) 0.70 (2) 1.09 (2) 1.03 (1) 0.00 (0)
Self-care - %(n)*
No problem 94.01 (1,130) 84.43 (103) 84.51 (240) 75.54 (139) 67.01 (65) 75.00 (21)
Slight problem 4.74 (57) 13.11 (16) 9.51 (27) 14.67 (27) 17.53 (17) 14.29 (4)
Moderate problem 1.25 (15) 1.64 (2) 4.58 (13) 8.15 (15) 13.40 (13) 7.14 (2)
Severe problem 0.00 (0) 0.00 (0) 1.41 (4) 0.54 (1) 2.06 (2) 3.57 (1)
Unable to do it 0.00 (0) 0.82 (1) 0.00 (0) 1.09 (2) 0.00 (0) 0.00 (0)
Usual Activities -
%(n)*
No problem 62.48 (751) 43.44 (53) 40.85 (116) 27.17 (50) 19.79 (19) 21.43 (6)
Slight problem 25.54 (307) 27.87 (34) 27.46 (78) 32.61 (60) 33.33 (32) 35.71 (10)
Moderate problem 9.32 (112) 22.13 (27) 25.00 (71) 27.72 (51) 30.21 (29) 28.57 (8)
Severe problem 1.91 (23) 4.10 (5) 5.63 (16) 10.87 (20) 13.54 (13) 14.29 (4)
Unable to do it 0.75 (9) 2.46 (3) 1.06 (3) 1.63 (3) 3.12 (3) 0.00 (0)
Pain/Discomfort -
%(n)*
No problem 33.69 (405) 13.11 (16) 16.25 (46) 8.70 (16) 10.31 (10) 3.57 (1)
Slight problem 43.43 (522) 38.52 (47) 40.99 (116) 29.89 (55) 25.77 (25) 42.86 (12)
Moderate problem 18.80 (226) 36.07 (44) 31.45 (89) 38.59 (71) 43.30 (42) 32.14 (9)
Severe problem 43 (3.58) 12.30 (15) 10.25 (29) 17.39 (32) 16.49 (16) 17.86 (5)
Extreme problem 0.50 (6) 0.00 (0) 1.06 (3) 5.43 (10) 4.12 (4) 3.57 (1)
Anxiety/Depression -
%(n)*
No problem 58.65 (705) 47.54 (58) 47.89 (136) 36.96 (68) 37.50 (36) 50.00 (14)
Slight problem 27.95 (336) 31.97 (39) 33.45 (95) 34.78 (64) 33.33 (32) 35.71 (10)
Moderate problem 11.56 (139) 18.85 (23) 16.90 (48) 21.20 (39) 18.75 (18) 7.14 (2)
Severe problem 1.66 (20) 0.00 (0) 1.76 (5) 5.98 (11) 8.33 (8) 7.14 (2)
Extreme problem 0.17 (2) 1.64 (2) 0.00 (0) 1.09 (2) 2.08 (2) 0.00 (0)
EQ-5D-5L - mean
(SD) 0.835 (0.132) 0.757 (0.161) 0.755 (0.167) 0.672 (0.221) 0.652 (0.230) 0.657 (0.191)
PAID-5 - mean (SD)* 3.57 (3.92) 5.02 (4.51) 4.95 (4.43) 6.18 (4.93) 6.88 (5.04) 6.70 (4.93)
*p<0.001: Overall statistical analysis
Neuro: neuropathy; PVD: peripheral vascular disease; SF-12v2: short-form-12 version 2; PF: physical functioning; RP: role
limitation due to physical problems; BP: bodily pain; GH: general health; VT: energy and vitality; SF: social functioning; RE: role
limitation due to emotional problems; MH: mental health; PCS: physical component summary; MCS: mental component summary;
EQ-5D-5L: Euroqol -5D Health utility index; PAID-5: Short form of the Problem Area in Diabetes Scale; SD: standard deviation
46
Table 3.3. Results of multiple linear regression of SF-12v2 (MCS and PCS)
Variables SF-12v2 - MCS SF-12v2 - PCS
Coefficient SE 95%CI p-value Coefficient SE 95% CI p-value
Foot problems (ref: no foot problem)
- Neuropathy -1.29 0.86 (-2.98, 0.40) 0.13 -2.70 0.87 (-4.42, -0.99) 0.002
- PVD -2.59 0.58 (-3.73, -1.46) <0.001 -3.96 0.62 (-5.17, -2.74) <0.001
- Neuropathy and PVD -2.98 0.75 (-4.44, -1.51) <0.001 -5.33 0.75 (-6.80, -3.86) <0.001
- Ulcer -4.58 1.02 (-6.59, -2.58) <0.001 -8.16 1.03 (-10.18, -6.13) <0.001
- Amputation -3.62 1.49 (-6.54, -0.70)) 0.02 -10.48 1.79 (-13.99, -6.97) <0.001
Age 0.18 0.02 (0.14, 0.22) <0.001 -0.01 0.02 (-0.05, 0.03) 0.73
Male 0.78 0.43 (-0.06, 1.61) 0.07 1.15 0.42 (0.32, 1.98) 0.01
Married 1.60 0.48 (0.66, 2.55) <0.001 1.48 0.49 (0.52, 2.43) 0.003
High school or more 1.91 0.55 (0.83, 2.99) <0.001 2.33 0.59 (1.17, 3.50) <0.001
Income >= $80,000 1.30 0.50 (0.33, 2.29) 0.01 2.38 0.49 (1.43, 3.34) <0.001
Race (ref: Caucasian)
- Aboriginal 2.24 1.33 (-0.38, 4.85) 0.09 4.56 1.16 (2.29, 6.83) <0.001
- Others -1.15 0.72 (-2.56, 0.27) 0.11 -0.17 0.72 (-1.58, 1.24) 0.81
Smoking (ref: no smoker)
- current smoker -1.62 0.73 (-3.05, -0.18) 0.03 -1.68 0.72 (-3.09, -0.28) 0.02
- Past smoker 0.68 0.43 (-0.17, 1.52) 0.12 -0.39 0.43 (-1.23, 0.46) 0.37
Insulin use -1.84 0.44 (-2.71, -0.97) <0.001 -2.03 0.45 (-2.91, -1.15) <0.001
Medical conditions -1.04 0.13 (-1.30, -0.78) <0.001 -1.82 0.13 (-2.07, -1.56) <0.001
Intercept 37.99 1.60 (34.85, 41.12)
49.72 1.63 (46.52, 52.92)
R-squared 0.15
0.28
Ref: reference group; PVD: peripheral vascular disease; SF-12v2: short-form-12 version 2; MCS: mental component summary; PCS: physical component summary; SE: standard
error; 95%CI: 95% confidence interval
47
Table 3.4. Results of multiple linear regression of EQ-5D-5L index and PAID-5 score
Variables EQ-5D-5L index score PAID-5 score
Coefficient SE 95%CI p-value Coefficient SE 95% CI p-value
Foot problems (ref: no foot problem)
- Neuropathy -0.052 0.014 (-0.080, -0.024) <0.001 1.13 0.42 (0.30, 1.95) 0.01
- PAD -0.052 0.010 (-0.072, -0.032) <0.001 1.56 0.28 (1.02, 2.10) <0.001
- Neuropathy and PAD -0.113 0.016 (-0.143, -0.082) <0.001 2.38 0.38 (1.63, 3.14) <0.001
- Ulcer -0.147 0.023 (-0.192, -0.102) <0.001 3.02 0.49 (2.06, 3.98) <0.001
- Amputation -0.127 0.034 (-0.192, -0.061) <0.001 2.26 0.86 (0.57, 3.94) 0.01
Age 0.001 0.000 (0.000, 0.001) 0.05 -0.10 0.01 (-0.12, -0.08) <0.001
Male 0.015 0.007 (0.001, 0.028) 0.04 -0.21 0.20 (-0.60, 0.18) 0.29
Married 0.009 0.008 (-0.008, 0.025) 0.30 -0.34 0.22 (-0.78, 0.10) 0.13
High school or more 0.035 0.010 (0.014, 0.055) 0.001 -0.81 0.27 (-1.35, -0.27) 0.003
Income >= $80,000 0.031 0.008 (0.016, 0.046) <0.001 -0.66 0.23 (-1.11, -0.21) 0.004
Race (ref: Caucasian)
- Aboriginal 0.086 0.016 (0.055, 0.117) <0.001 -0.83 0.58 (-1.98, 0.31) 0.15
- Others 0.022 0.011 (0.002, 0.043) 0.04 0.95 0.42 (0.12, 1.77) 0.02
Smoking (ref: no smoker)
- current smoker -0.026 0.013 (-0.051, -0.001) 0.04 0.10 0.36 (-0.60, 0.80) 0.77
- Past smoker -0.015 0.007 (-0.028, -0.001) 0.04 -0.40 0.20 (-0.78, -0.01) 0.05
Insulin use -0.032 0.008 (-0.048, -0.017) <0.001 1.07 0.21 (0.66, 1.47) <0.001
Medical conditions -0.027 0.002 (-0.032, -0.022) <0.001 0.19 0.06 (0.06, 0.32) 0.003
Intercept 0.837 0.029 (0.781, 0.893)
10.38 0.78 (8.86, 11.90)
R-squared 0.25
0.15
Ref: reference group; PVD: peripheral vascular disease; EQ-5D-5L: Euroqol -5D Health utility index; PAID-5: Short form of the Problem Area in Diabetes Scale; SE: standard
error; 95%CI: 95% confidence interval
48
3.3.3. Multiple Linear Regression Analysis
Table 3.3 shows the results of the regression analysis for the summary components of the SF-12.
After controlling for socio-demographic and other medical conditions, participants with ulcer
had the largest decrement in MCS score (-4.58, p<0.001) followed by patients reporting
amputation (-3.62, p=0.02). Those with neuropathy and PVD (-2.98, p<0.001) had lower MCS
score than individuals with either neuropathy or PVD. However, this summary score in
participants with diabetic neuropathy were not statistically different from those without foot
complications.
Foot problems were associated with a significant decrement in PCS scores. In particular,
participants with an amputation had a 10 units lower PCS score than those without foot problems.
A decrement on physical health was also found in the group reporting ulceration. Participants
reporting both risk factors for ulceration had lower physical health than those without any
problems. In addition, the decrements reported for PVD were around 4 points while participants
with neuropathy had a decrement of 2.70 (Table 3.3).
Table 3.4 shows foot problems were statistically associated with higher PAID-5 scores, after
controlling for possible confounders. Individuals with ulceration had higher decrements followed
by individuals reporting both neuropathy and PVD.
Compared to subjects without foot problems, those with foot conditions had significantly lower
EQ-5D index scores. Among them, subjects with ulcer had the largest decrement (-0.147,
p<0.001) followed by those with amputation (-0.127, p<0.001). Neuropathy and PVD had a
similar decrement of 0.05 in the EQ-5D index score. The index score, measured by the EQ-5D-
5L, was better for male participants as well as those with higher education and income. Number
of medical conditions, and use of insulin were significantly associated with lower index scores
(Table 3.4).
3.4. Discussion
This study examined the HRQOL of adults with type 2 diabetes reporting various foot problems,
and compared them to those without foot problems. We found that individuals with type 2
diabetes reporting foot problems have lower physical, mental and overall perceived health
49
compared to those with no foot problems. Participants reporting both risk factors (neuropathy
and PVD) for ulceration had lower HRQOL measurements than participants reporting only one
of them. Among foot problems, ulcer was associated with the highest distress, lowest MCS and
EQ-5D-5L index scores, while amputation was associated with the largest decrement in PCS.
Our study found similar results to other studies reporting decrements on physical health of
patients with ulcer and amputation23-26
. Altenburg et al found no differences in mental health,
measured with the SF-12, between patients with and without foot ulcer, while other studies
reported lower mental health in patients with ulceration23, 24, 26, 27
. The differences may be due to
study settings, presence of other comorbidities and ulcer severity, etiology and duration. Our
analysis found that participants with ulcer had the lowest MCS scores and the results are
supported by the higher PAID-5 index score, a specific measure of distress related to diabetes.
Ragnarson-Tennvall et al found that individuals with ulceration had lower EQ-5D index score
than those who underwent minor amputation, but higher than those with a major amputation28
.
An explanation for our results could be associated with a low percentage of major amputation in
our sample. However, we cannot test this hypothesis as the survey did not ask about the type of
amputation participants underwent. It is also important to notice that our study and the one from
Ragnarson-Tennvall et al included low numbers of individuals who had an amputation28
. Overall,
studies on diabetic amputations had several methodological issues (i.e. small sample size, use of
proxy HRQOL measures and highly selected patients) and further analysis are required for any
conclusions10, 28, 29
.
Three studies on neuropathy reported no significant differences on MCS scores between patients
with and without neuropathy, which is in line with our findings30-32
. One explanation could be
that the SF-12 as a generic measure is not able to capture mental issues specifically associated
with this disease33, 34
. Once we look at the specific measure of PAID-5, we see that this foot
condition is associated with diabetes-related distress. Another point is that neuropathy is a
condition that gradually changes in symptoms and manifestation through time and our analysis is
based on one measure at one point in time35
.
The lower PCS scores in individuals reporting ulcer or amputation are explained by their
negative effects on mobility and engagement with daily activities33, 36
. Based on interviews,
individuals with ulceration also felt more anxious and scared of further potential trauma which
50
compromised their physical functions37
. Both group of individuals likewise had reduced MCS
scores, which were more pronounced in those with ulceration. Problems in mental health in
individuals reporting an amputation have been linked to the changes in body image, physical and
social limitations38, 39
. These patients often express lack of social activities and feelings of
isolation40
. One study found that compared to controls, amputation was associated with more
negative feelings towards the foot and dissatisfaction with life35, 41
. The same study also reported
that those with ulceration had an even more significant negative feeling toward the foot than both
groups formerly mentioned41
. Possible explanations are that individuals with ulcer have stated
loss of hope on treatment success, frustration and emotional instability associated with the
constant visits to health-care providers, changes in dressing and use of footwear35, 36, 41
.
The true prevalence of PVD in the diabetic population remains unclear 42
. This condition’s
impact on HRQOL measurements is understudied, though we found that PVD decrements
different domains on mental, physical and overall health.
For our analysis, we made assumptions based on the pathophysiology of ulceration and
amputation in diabetes. Around 85% of amputations are preceded by ulcerations and 78% of
subjects with neuropathy will develop ulcers43, 44
. We assumed that amputation and ulceration
would be the main causes of negative effects on HRQOL. On the other hand, we know that: (1)
some patients could have had both amputation and ulceration at the same time, though we
assume that patients reporting both, would have amputation as the main cause effecting HRQOL
as did Ragnarson-Tennvall28
; (2) similarly, we assumed that foot ulcers would cause the main
and same effects on HRQOL, regardless of the presence of different risk factors (neuropathy and
PVD). The study design and sample size did not allow us to have more detailed analysis and
obtain evidences to further validate our assumptions and results. We also could not find
longitudinal studies on HRQOL of diabetic patients at high risk further developing ulcers and
amputations to compare our findings. Though we understand this type of study would require
many resources, it would improve our knowledge on HRQOL and clinical pathway of foot
problems.
The study strengths include the use of a large population-based sample and the use of different
types of HRQOL measures. The generic measurements facilitate health professionals to compare
results across different diseases. In particular, the EQ-5D-5L index measurements can further be
51
used in cost-effectiveness studies of new interventions on diabetic foot. The index score was
based on the Canadian preference-based measures and on the 5L instruments that allow for lower
ceiling effect and description of 3,125 possible health states instead of 243 found in the previous
version. Another advantage is on the use of a diabetic-specific measure, the PAID-5, which
assess specific concerns related to diabetes that are not capture by generic instruments.
Although, the ABCD cohort used a comprehensive recruitment using several approaches, there
was a low number of the aboriginal and immigrant respondents. Our analysis showed that
aboriginals had better HRQOL measurements than Caucasians, which contradicts findings from
other studies45, 46
. These results are likely due to selection bias and small number of Aboriginal
people in this study.
The study also has other limitations. First, there is an association between diabetic foot problems
and quality of life but we cannot infer a causal relationship as this study used cross-sectional data.
Second, the characteristics and diabetic complications were self-reported and prone to
information bias, especially because neuropathy and PVD are asymptomatic conditions and the
prevalence of these diseases could be underestimated in our study. Third, there were not many
cases of reported amputations that could limit the generalizability of our results. Fourth, the
excluded sample was more educated and less distressed and this could bias our results. However,
we do not know the direction and influence of this exclusion as the foot status of this population
is unknown.
Another possible limitation is on the use of multiple linear regression for our statistical analysis
and the violation of homoscedasticity and normal distribution of residuals. Other authors have
suggested the use of generalized linear model with gamma distribution for EQ-5D index scores,
which we conducted separately (Appendix B). Though the statistical significance of age, other
races and past smokers were different between both models as the p-value was close to 0.05,
little difference was found in the regression coefficients. Therefore, we found that the multiple
linear regression coupled with robust standard error would be a valid approach and simplify the
consistence and interpretation of our results. Studies around this area have demonstrated that this
approach remains valid in large samples22, 47
.
Higher income and education were associated with higher HRQOL, while insulin use, diabetic
complications and other medical conditions had negative effects on HRQOL measures. Other
52
studies in adults with type 2 diabetes have also found similar results regarding the socio-
demographic variables48-50
. Studies regarding diabetic comorbidities have varied in settings and
how researchers define and categorize them. As a result, comparison of results can become an
issue. We constructed models with each individual comorbidity (Appendix C) instead of a
summary variable as we presented in the results section. The decrements of foot problems were
smaller, but the models gave the same conclusions as the ones previously reported and little
increment was seen in the explained variance given by the adjusted r-squared. In addition, some
medical conditions were not statistically significant (i.e. retinopathy, hypertension).
Consequently, we opted for the models with medical conditions as a continuous variable to
improve the power of our analysis.
Finally, we did not include in our analysis, data on glycated hemoglobin, BMI and diabetes
duration. Studies have shown that patients with controlled diabetes measured by glycated
hemoglobin present better quality of life 51, 52
. Though, it remains controversial as some argue
that the reason is the decrease in number of complications53, 54
. We built other models that
included diabetes duration as an independent variable (Appendix D). However, there was a large
number of missing data on this variable (23.57%) and those participants were less educated, non-
white, not married and more distressed as measured by PAID-5 (Appendix E). We assumed that
missing data was not completely at random. Since the inclusion of this variable would decrease
analytical power while increasing bias and the standard error, we decided to exclude it from our
model.
3.5. Conclusion
People with diabetic foot complications report lower HRQOL compared to the diabetic patients
without foot complications. These findings support the view that diabetic patients with chronic
wounds and amputation need health professional assistance and community support to improve
quality of life. Additionally, patients at high risk of ulceration, in which neuropathy and PVD are
present, have also problems in several domains of HRQOL and there should be interventions
also targeting these populations.
53
3.6. References
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2. Public Health Agency of Canada. Diabetes in Canada: Facts and figures from a public
health perspective. Ottawa2011.
3. Evans JM, Newton RW, Ruta DA, MacDonald TM, Morris AD. Socio-economic status,
obesity and prevalence of Type 1 and Type 2 diabetes mellitus. Diabetic Medicine: A Journal Of
The British Diabetic Association. 2000;17:478-480.
4. Statistics Canada. CANSIM table 102-0561: Leading cause of death by sex (both
sexes)2015.
5. Sheri LM, Feeny DH, Johnson JA. Health-Related Quality of Life Deficits Associated
with Diabetes and Comorbidities in a Canadian National Population Health Survey: Springer;
2005:1311.
6. Adler AI, Boyko EJ, Ahroni JH, Smith DG. Lower-extremity amputation in diabetes: the
independent effects of peripheral vascular disease, sensory neuropathy, and foot ulcers. Diabetes
Care. 1999;22:1029-1035.
7. Boulton AJM, Cavanagh PR, Rayman G. - The foot in diabetes Y1 - 2006. - Diabetes in
practice.- 449.
8. Reiber GE, Vileikyte L, Boyko EJ, et al. Causal pathways for incident lower-extremity
ulcers in patients with diabetes from two settings. Diabetes Care. 1999;22:157-162.
9. Pecoraro RE, Reiber GE, Burgess EM. Pathways to diabetic limb amputation. Basis for
prevention. Diabetes Care. 1990;13:513-521.
10. Hogg FRA, Peach G, Price P, Thompson MM, Hinchliffe RJ. Measures of health-related
quality of life in diabetes-related foot disease: a systematic review. Diabetologia. 2012;55:552-
565.
11. Goodridge D, Trepman E, Embil JM. Health-related quality of life in diabetic patients
with foot ulcers: literature review. Journal Of Wound, Ostomy, And Continence Nursing:
Official Publication Of The Wound, Ostomy And Continence Nurses Society / WOCN.
2005;32:368-377.
54
12. Janssen MF, Lubetkin EI, Sekhobo JP, Pickard AS. The use of the EQ-5D preference-
based health status measure in adults with Type 2 diabetes mellitus. Diabetic Medicine.
2011;28:395-413.
13. Al Sayah F, Soprovich A, Qiu W, Edwards AL, Johnson JA. Diabetic Foot Disease, Self-
Care and Clinical Monitoring in Adults with Type 2 Diabetes: The Alberta's Caring for Diabetes
(ABCD) Cohort Study. Can J Diabetes. 2015;39 Suppl 3:S120-126.
14. Al Sayah F, Majumdar SR, Soprovich A, et al. The Alberta's Caring for Diabetes
(ABCD) Study: Rationale, Design and Baseline Characteristics of a Prospective Cohort of
Adults with Type 2 Diabetes. Can J Diabetes. 2015;39 Suppl 3:S113-119.
15. Ware JE, Kosinski M, Keller SD. A 12-Item Short-Form Health Survey: Construction of
Scales and Preliminary Tests of Reliability and Validity: J. B. Lippincott-Raven Publishers;
1996:220.
16. Herdman M, Gudex C, Lloyd A, et al. Development and preliminary testing of the new
five-level version of EQ-5D (EQ-5D-5L). Qual Life Res. 2011;20:1727-1736.
17. Xie F, Pullenayegum E, Gaebel K, et al. A Time Trade-off-derived Value Set of the EQ-
5D-5L for Canada. Medical Care. 2016;54:98-105.
18. Fleishman JA, Selim AJ, Kazis LE. Deriving SF-12v2 physical and mental health
summary scores: a comparison of different scoring algorithms. Quality of Life Research.
2010;19:231-241.
19. McGuire BE, Morrison TG, Hermanns N, et al. Short-form measures of diabetes-related
emotional distress: the Problem Areas in Diabetes Scale (PAID)-5 and PAID-1 (English).
Diabetologia (Berlin). 2010;53:66-69.
20. Watkins K, Connell CM. Measurement of Health-Related QOL in Diabetes Mellitus.
PharmacoEconomics. 2004;22:1109-1126.
21. Barzi F, Woodward M. Imputations of missing values in practice: Results from
imputations of serum cholesterol in 28 cohort studies. American Journal of Epidemiology.
2004;160:34-45.
55
22. Pullenayegum EM, Tarride J-E, Feng X, Goeree R, Gerstein HC, O'Reilly D. Analysis of
Health Utility Data When Some Subjects Attain the Upper Bound of 1: Are Tobit and CLAD
Models Appropriate? Value in Health. 2010;13:487-494.
23. Ali Alzahrani HS, M. G. The impact of religious connectedness on health-related quality
of life in patients with diabetic foot ulcers. J Relig Health. 2013;52:840-850.
24. Altenburg NJ, P.;Barthel, A.;Bittner, A.;Pöhlmann, K.;Rietzsch, H.;Fischer,
S.;Mennicken, G.;Koehler, C.;Bornstein, S. R. Alcohol consumption and other psycho-social
conditions as important factors in the development of diabetic foot ulcers. Diabetic Medicine.
2011;28:168-174.
25. Ribu LH, B. R.;Moum, T.;Birkeland, K.;Rustoen, T. A comparison of the health-related
quality of life in patients with diabetic foot ulcers, with a diabetes group and a nondiabetes group
from the general population. Quality of Life Research. 2007;16:179-189.
26. Valensi PG, I.;Baron, F.;Moreau-Defarges, T.;Guillon, P. Quality of life and clinical
correlates in patients with diabetic foot ulcers. Diabetes and Metabolism. 2005;31:263-271.
27. Raspovic KMW, D. K. Self-reported quality of life and diabetic foot infections. Journal
of Foot and Ankle Surgery. 2014;53:716-719.
28. Ragnarson Tennvall GA, J. Health-related quality of life in patients with diabetes mellitus
and foot ulcers. Journal of Diabetes and its Complications. 2000;14:235-241.
29. Boutoille D, Féraille A, Maulaz D, Krempf M. Quality of life with diabetes-associated
foot complications: comparison between lower-limb amputation and chronic foot ulceration.
Foot & Ankle International. 2008;29:1074-1078.
30. TH I, Schaper NC, Melai T, Meijer K, Willems PJ, Savelberg HH. Lower extremity
muscle strength is reduced in people with type 2 diabetes, with and without polyneuropathy, and
is associated with impaired mobility and reduced quality of life. Diabetes Res Clin Pract.
2012;95:345-351.
31. Lewko J, Polityńska B, Kochanowicz J, et al. Quality of life and its relationship to the
degree of illness acceptance in patients with diabetes and peripheral diabetic neuropathy.
Advances In Medical Sciences. 2007;52 Suppl 1:144-146.
56
32. Van Acker KB, D.;De Bacquer, D.;Weiss, S.;Matthys, K.;Raemen, H.;Mathieu, C.;Colin,
I. M. Prevalence and impact on quality of life of peripheral neuropathy with or without
neuropathic pain in type 1 and type 2 diabetic patients attending hospital outpatients clinics.
Diabetes and Metabolism. 2009;35:206-213.
33. Goodridge D, Trepman E, Sloan J, et al. Quality of life of adults with unhealed and
healed diabetic foot ulcers. Foot Ankle Int. 2006;27:274-280.
34. Vileikyte L, Peyrot M, Bundy C, et al. The development and validation of a neuropathy-
and foot ulcer-specific quality of life instrument. Diabetes Care. 2003;26:2549-2555.
35. Price P. The Diabetic Foot: Quality of Life: University of Chicago Press; 2004:S129.
36. Brod M. Quality of life issues in patients with diabetes and lower extremity ulcers:
patients and care givers. Qual Life Res. 1998;7:365-372.
37. Ashford R, McGee P, Kinmond K. Perception of quality of life by patients with diabetic
foot ulcers. Diabetic Foot Journal. 2000;3:150-155.
38. Horne C, Neil J. Quality of life inpatients with prosthetic legs: a
comparison study. Journal Prosthetics Orthotics 2009;21:154-159.
39. Gallagher P, O'Donovan MA, Doyle A, Desmond D. Environmental barriers, activity
limitations and participation restrictions experienced by people with major limb amputation.
Prosthet Orthot Int. 2011;35:278-284.
40. Kinmond K, McGee P, Gough S, Ashford R. 'Loss of self': a psychosocial study of the
quality of life of adults with diabetic foot ulceration. J Tissue Viability. 2003;13:6-8, 10, 12
passim.
41. Carrington AL, Mawdsley SK, Morley M, Kincey J, Boulton AJ. Psychological status of
diabetic people with or without lower limb disability. Diabetes Res Clin Pract. 1996;32:19-25.
42. Peripheral Arterial Disease in People With Diabetes. Diabetes Care. 2003;26:3333-3341.
43. Reiber GE, Ledoux WR. - Epidemiology of Diabetic Foot Ulcers and Amputations:
Evidence for Prevention Y1 - 2002; 2003. - The Evidence Base for Diabetes Care.- 641.
57
44. Rebolledo FA, Teran Soto JM, de la Pena JE. The Pathogenesis of the Diabetic Foot
Ulcer: Prevention and Management. InTech. 2011:155-182.
45. Thommasen HV, Berkowitz J, Thommasen AT, Michalos AC. Understanding
relationships between diabetes mellitus and health-related quality of life in a rural community.
Rural Remote Health. 2005;5:441.
46. Johnson JA, Nowatzki TE, Coons SJ. Health-related quality of life of diabetic Pima
Indians. Med Care. 1996;34:97-102.
47. Long JS, Ervin LH. Using Heteroscedasticity Consistent Standard Errors in the Linear
Regression Model: American Statistical Association; 2000:217.
48. Imayama I, Plotnikoff RC, Courneya KS, Johnson JA. Determinants of quality of life in
type 2 diabetes population: the inclusion of personality. Qual Life Res. 2011;20:551-558.
49. Maddigan SL, Feeny DH, Majumdar SR, Farris KB, Johnson JA. Understanding the
determinants of health for people with type 2 diabetes. American Journal of Public Health.
2006;96:1649-1655.
50. Zhang PB, M. B.;Bilik, D.;Ackermann, R. T.;Li, R.;Herman, W. H. Health Utility Scores
for People With Type 2 Diabetes in U.S. Managed Care Health Plans Results from Translating
Research Into Action for Diabetes (TRIAD). Diabetes Care. 2012;35:2250-2256.
51. Ali MK, Feeney P, Hire D, et al. Glycaemia and correlates of patient-reported outcomes
in ACCORD trial participants. Diabetic Medicine: A Journal Of The British Diabetic
Association. 2012;29:e67-e74.
52. Van der Does FEE, De Neeling JND, Snoek FJ, et al. Symptoms and well-being in
relation to glycemic control in type II diabetes. Diabetes Care. 1996;19:204-210.
53. Quality of life in type 2 diabetic patients is affected by complications but not by intensive
policies to improve blood glucose or blood pressure control (UKPDS 37). U.K. Prospective
Diabetes Study Group. Diabetes Care. 1999;22:1125-1136.
54. Jacobson AM. Impact of improved glycemic control on quality of life in patients with
diabetes. Endocrine Practice: Official Journal Of The American College Of Endocrinology And
The American Association Of Clinical Endocrinologists. 2004;10:502-508.
58
Chapter 4. General Discussion and Conclusion
4.1. Summary of Findings
In Alberta in 2014, 171,906 individuals were estimated to have diabetes, a condition that
represents a major burden in Canada1-3
. People with type 2 diabetes are at greater risk of
developing foot problems ranging from loss of protection, caused by diabetic neuropathy, to
ulceration, which could ultimately lead to an amputation4, 5
. These different conditions vary in
presentation, symptomatology and could be associated with decrements in different health
domains. To address the impact diabetic foot problems have on health-related quality of life
(HRQOL), we performed a systematic review (Chapter 2) and a cross-sectional analysis of
HRQOL among individuals with type 2 diabetes in Alberta (Chapter 3).
In chapter 2, we conducted a systematic review according to the PRISMA6 and Cochrane
handbook guidelines7 including 21 and 8 studies for qualitative and quantitative synthesis,
respectively. A total of 10 different instruments were employed, but we did not include all of
them into the meta-analysis due to possibilities of greater heterogeneity and inconsistence. Only
studies assessing health domains of the SF-36/12 were pooled as majority of studies used them
as a measurement of effect.
We found that different foot problems (neuropathy, peripheral vascular disease (PVD), ulcer and
amputation) are associated with reduced HRQOL. Neuropathy had statistically non-significant
small effect sizes in most domains of the SF-36/12, apart from the small-medium effect sizes of
physical functioning domain and physical summary score (PCS). On the other hand, ulcer had a
small-medium effect size in vitality, role emotional, mental health and mental component
summary (MCS), though mental health did not achieve statistical significance. It also had a
medium-large effect size that was statistically significant in physical functioning, role physical,
bodily pain, general health, social functioning and PCS. Amputation was associated with
decrements on HRQOL, but results were conflicting on whether the transition of foot ulcer to
amputation was associated with higher decrements in HRQOL. There was a lack of evidence for
an association of HRQOL and Charcot foot and PVD. Only two studies measure this association
and they were cross-sectional with the presence of confounding variables8, 9
.
59
To provide results in a population-based sample and HRQOL of individuals with type 2 diabetes
reporting foot problems, we examined the cross-sectional data obtained from the self-
administered survey from the Alberta’s Caring for Diabetes (ABCD) study10, 11
(chapter 3). It
included 1,935 individuals with majority of them presenting PVD (29.15%) and neuropathy
(19.17%). There were few self-report of foot ulcer (6.10%) and amputation of limbs (1.45%).
Socio-demographic and clinical characteristics such as marital status, gender, education, income,
medical conditions and insulin use were associated with HRQOL. Neuropathy was associated
with significant decrements of PCS, EQ-5D index and PAID-5 scores. No differences were
found in MCS between individuals with neuropathy and no foot complications. Individuals
reporting either PVD, ulcer or amputation had statistically significant lower HRQOL measured
through SF-12 (PCS, MCS), EQ-5D and PAID-5 than those with no foot complications.
Participants reporting both neuropathy and PVD had more decrements on health compared to
individuals reporting one of these conditions. While amputation was associated with the highest
decrement on physical health with a 10-unit decrease in this SF-12 domain, patients reporting
ulceration had the lowest mental and perceived health.
4.2. Discussion
This thesis has studied various foot conditions commonly found in patients with diabetes and
their association with different decrements in health domains measured through generic and
specific instruments. The systematic review and cross-sectional analysis showed that neuropathy
is not statistically associated with lower MCS scores, but the condition had a significant impact
on PCS scores in patients with diabetes. However, our analysis reported that when measured
with a diabetes-specific measure and accounting for potential confounders, individuals with
neuropathy presented significantly higher diabetes-related distress compared to individuals with
diabetes and no diagnosed foot problems. Some authors argue for the lack of sensitivity of the
SF-36/12 to capture mental issues related to neuropathy in people with diabetes12, 13
.
Interestingly, our data analysis showed significant decrements due to neuropathy in EQ-5D index
score, another generic instrument. More than half of individuals with neuropathy (52.5%)
reported some level of anxiety/depression. 20.5% of them had moderate to extreme problems of
60
anxiety/depression, while 13.4% of individuals with no foot complications reported moderate to
extreme problems in this EQ-5D dimension.
The reduced EQ-5D index score in participants with neuropathy could also be due to the physical
delimitation of this condition and the fact that this utility instrument has shown great
psychometric properties in physical conditions14
. Since EQ-5D has also limited evidence on
mental health14
, a specific instrument for this domain, such as the PAID-5 could be an alternative
or complement, though further studies in this area are necessary.
The systematic review pointed to the lack of specific HRQOL measurement for PVD in type 2
diabetes which we covered in the cross-sectional data analysis. Additionally, an important
finding was that participants with both risk factors, neuropathy and PVD were associated with
higher decrements on physical, mental and overall health than participants with either of the
condition. Even though the true prevalence of these risk factors in the diabetic population is
unknown, most individuals developing ulcer have the neuroischemic type15, 16
, an indication that
the presence of neuropathy along with PVD might be a common situation in patients with
diabetes and future studies on HRQOL should take this into account.
The cross-sectional analysis tried to address the magnitude of the impact amputation has on
different health domains as we found conflicting results from our systematic review. Assuming
loss of limbs as the endpoint of the diabetic foot clinical pathway, we can see a decrement on
physical health across this pathway in which the advance of foot disease correlates with the
deterioration on this health domain. A different scenario is pointed in preference-based and
mental health measures as individuals with foot ulcer had worse scores in these measurements
instead of those with amputation. Although, the analysis had statistically significant results, both
conducted studies in this thesis had problems regarding sample size of this foot problem.
Qualitative research also supports our findings from both studies that participants diagnosed with
diabetes with foot ulcers and amputation have lower perspectives on their health. A qualitative
research explains that patients with diabetic foot ulcer had a very negative attitude towards the
foot with requirements for extensive care and hospital visits17
. Loss of hope on treatment success,
dissatisfaction with life were seen in patients with an amputation and foot ulcer, with the later
reporting more often17, 18
.
61
The fact that our two studies found better mental health in patients with amputation than those
with an ulcer, however, does not translate into amputation being a gold standard treatment for
ulceration. Our studies found significant decrements in physical, perceived health and higher
distress compared to diabetic patients with no self-report of foot problems. One study reported
that 50% of a sample of amputees were at high risk of psychiatric disorders as these patients felt
imprisoned into their houses and socially isolated19
. In addition, a major amputation is also
associated with reduced survival rates20, 21
.
The strength of the first study lies on the conduction of a systematic review which methodically
combines and synthesizes the current HRQOL literature. It has the advantage to report results
based on more than one single study, find the inconsistencies and current gaps in knowledge on
diabetic foot diseases and HRQOL. This systematic review attempted to cover the main scientific
databases and carry a search with the guidance of an experienced librarian. The whole process
was in accordance with the PRISMA6, 22
and Cochrane handbook7 with two independent
researchers assessing and including studies to reduce research bias and opinion of a single person.
The systematic review also attempted to find measurements not affected by information bias,
which is likely present in the cross-sectional analysis as the results were dependent of
participants’ self-report.
The data analysis was the first study that we have an acknowledgment of comparing different
diabetic foot problems and their HRQOL, based on different instruments, in a population of
diabetes type 2 living in Alberta. It allows us to observe the health status of this population and
whether different stages of foot severity should be targeted more specifically to better meet their
health-care needs. The strength of this study lies in its large sample size and extensive
recruitment programs to have a sample representative of the population of type 2 diabetes in
Alberta. The assessment of utility measures, based on the EQ-5D-5L, can further be used in
economic evaluation of interventions for diabetic foot conditions. It attempted to find an
association between HRQOL measures and PVD, since the systematic view pointed to the lack
of reports regarding this foot problem.
Both studies also had several limitations. The issues on the systematic review were mainly due to
constrained resources as: (1) we did not search the grey literature; (2) contacted the authors for
additional information; (3) restricted to articles published in three languages (English, Spanish
62
and Portuguese). Another concern was the conduction of meta-analysis with high heterogeneity
among studies and the use of standardized mean difference as a measure of effect instead of
minimal clinical difference as some other authors have suggested23, 24
.
The cross-sectional analysis had limitations worth mentioning as: (1) the use of self-report
conditions; (2) possible effect of confounding variables (HbA1c, BMI and diabetes duration);
and (3) exclusion of 135 participants due the use of different outcome measures that were also
more educated and less distressed at the final analysis.
The systematic review and data-analysis were limited to lack of causal inference as both studies
based their conclusions on cross-sectional data, and small sample size of patients with diabetes
undergoing an amputation.
4.3. Conclusion and Future Research
The ABCD analysis was an attempt to cover some knowledge gaps as the lack of studies on
diabetic foot disease in Alberta, lack of measurements with a disease-specific instrument and
quantitative measures of the effect of PVD in HRQOL. Both studies found that diabetic foot
complications are associated with lower HRQOL with the advancing conditions correlating with
lower physical health. Our cross-sectional analysis results showed that while amputation had the
lowest scores in physical health, ulceration was associated with the highest decrements in
perceived and mental health.
There is potential to improve HRQOL in participants with diabetes reporting foot problems by
preventing future deterioration of the foot and leading to worse stages of ulceration and
amputation. Current guidelines recommend the screening of neuropathy with simple instruments
such as the 10g monofilament, and PVD at least on a yearly basis25-27
. There are no evidence
showing that the screening per se improves HRQOL, but the detection of these early stages and
proper referral could prevent development of foot ulceration and further decrements on physical
and mental health described in our cross-sectional data of participants with diabetes. Early stages
of diabetic foot problems such as neuropathy and PVD are not routinely checked in Alberta10, 28
.
Care on these conditions are usually neglected10, 28
even though our results indicate experience of
lower physical, mental and overall health. Community support and other effective measures
63
should be put into practice to improve HRQOL of the screened participants for neuropathy
and/or PVD.
Another importat strategy in targeting HRQOL improvement is in understanding the effect of
modifiable risk-factors on health domains in participants with diabetic foot problems.
Unfortumately, the data analysis and most of the included studies of the systematic review
evaluated the effects of non-modifiable factors which cannot be changed. Future research on the
assessment of the effects of modifiable factors (i.e footcare and medical adherence) in HRQOL
on patients with foot problems are required.
The use of generic instruments such as SF-12 and EQ-5D are very informative for policy makers
as they give a general perception of individual’s health and comparability to other chronic
conditions. While the first mentioned measure allows for a profile of physical and mental health,
the latter as a preference-based measure can further be used in economic evaluation of future
interventions. Nonetheless, our study showed the importance of specific-measures and their
potential use to improve policies on mental health, supporting other authors who have suggested
the use of generic and specific instruments while measuring HRQOL29, 30
. Although, we
acknowledge that it comes with the costs of increase in response burden.
The findings in our studies support that medical perception on patient’s health and clinical
presentation such as loss of protection sensation or obstruction of blood flow are insufficient to
capture the burden of foot problems in diabetes. Only when measuring the individual domains of
HRQOL can we have the picture of the current situation and improve health policies and
interventions offered to the population with diabetes. For example, our results question the lack
of support, extension or effective interventions, mainly regarding mental health in patients with
diabetes and foot problems. Reasons could be: (1) most guidelines are based on weak evidence25-
27; (2) clinical pathways for diabetic foot are not put into practice
10, 28; (3) current guidelines
gives little importance in measuring the patient’s HRQOL25-27
; (4) lack of recommendation in
treatments for mental health.
Further cohort studies with longer follow up and larger amputation sample size are still required
to determine causality and the correlation of changes in HRQOL with different stages of diabetic
foot problems.
64
4.4. References
1. Statistics Canada. CANSIM table 102-0561: Leading cause of death by sex (both
sexes)2015.
2. Statistics Canada. CANSIM table 105-0501: Diabetes, by sex, provinces and
territories (Number of persons). http://www.statcan.gc.ca/tables-tableaux/sum-
som/l01/cst01/health54a-eng.htm: Statistics Canada; 2016.
3. International Diabetes Federation. IDF Diabetes Atlas. Vol 7th edition. Brussels2015.
4. Reiber GE, Vileikyte L, Boyko EJ, et al. Causal pathways for incident lower-extremity
ulcers in patients with diabetes from two settings. Diabetes Care. 1999;22:157-162.
5. Adler AI, Boyko EJ, Ahroni JH, Smith DG. Lower-extremity amputation in diabetes -
The independent effects of peripheral vascular disease, sensory neuropathy, and foot
ulcers. Diabetes Care. 1999;22:1029-1035.
6. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic
reviews and meta-analyses: the PRISMA statement. Ann Intern Med. 2009;151:264-269,
w264.
7. Higgins JPT, Green S, Cochrane C. - Cochrane handbook for systematic reviews of
interventions Y1 - 2005.
8. Wexler DJ, Grant RW, Wittenberg E, et al. Correlates of health-related quality of life in
type 2 diabetes. Diabetologia. 2006;49:1489-1497.
9. Raspovic KMW, D. K. Self-reported quality of life in patients with diabetes: A
comparison of patients with and without charcot neuroarthropathy. Foot and Ankle
International. 2014;35:195-200.
10. Al Sayah F, Soprovich A, Qiu W, Edwards AL, Johnson JA. Diabetic Foot Disease, Self-
Care and Clinical Monitoring in Adults with Type 2 Diabetes: The Alberta's Caring for
Diabetes (ABCD) Cohort Study. Can J Diabetes. 2015;39 Suppl 3:S120-126.
11. Al Sayah F, Majumdar SR, Soprovich A, et al. The Alberta's Caring for Diabetes
(ABCD) Study: Rationale, Design and Baseline Characteristics of a Prospective Cohort
of Adults with Type 2 Diabetes. Can J Diabetes. 2015;39 Suppl 3:S113-119.
12. Goodridge D, Trepman E, Sloan J, et al. Quality of life of adults with unhealed and
healed diabetic foot ulcers. Foot Ankle Int. 2006;27:274-280.
65
13. Vileikyte L, Peyrot M, Bundy C, et al. The development and validation of a neuropathy-
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Appendix
Appendix A. Results of Randon-effect Meta-analysis of SF-36/12 domains and
summary scores
A.1. Meta-analsys comparing SF-36/12 domains and summary scores between individuals
with and without foot ulcer
Physical functioning
Role Physical
Bodily Pain
83
General Health
Vitality
Social Functioning
Role Emotional
84
Mental Health
Physical Component Summary (PCS)
Mental Component Summary (MCS)
85
A.2. Meta-analysis comparing SF-36/12 domains and summary scores between individuals
with and without neuropathy
Physical Functioning
Role Physical
Bodily Pain
General Health
86
Vitality
Social Functioning
Role Emotional
Mental Health
87
Physical Component Summary (PCS)
Mental Component Summary (MCS)
88
Appendix B. Alternative statistical analysis of EQ-5D-5L index score
Variables EQ-5D-5L index score (robust standard error) EQ-5D-5L index score (GLM- gamma distribution)
Coefficient SE 95% CI p-value Coefficient SE 95% CI p-value
Foot problems (ref: no foot problem)
- Neuropathy -0.052 0.014 (-0.080, -0.024) <0.001 -0.052 0.015 (-0.081, -0.023) <0.001
- PVD -0.052 0.010 (-0.072, -0.032) <0.001 -0.055 0.011 (-0.076, -0.035) <0.001
- Neuropathy and PVD -0.113 0.016 (-0.143, -0.082) <0.001 -0.119 0.012 (-0.142, -0.096) <0.001
- Ulcer -0.147 0.023 (-0.192, -0.102) <0.001 -0.148 0.015 (-0.177, -0.120) <0.001
- Amputation -0.127 0.034 (-0.192, -0.061) <0.001 -0.123 0.026 (-0.173, -0.072) <0.001
Age 0.001 0.000 (0.000, 0.001) 0.05 0.001 0.000 (0.000, 0.002) 0.01
Male 0.015 0.007 (0.001, 0.028) 0.04 0.016 0.008 (0.001, 0.031) 0.04
Married 0.009 0.008 (-0.008, 0.025) 0.30 0.009 0.008 (-0.008, 0.025) 0.30
High school or more 0.035 0.010 (0.014, 0.055) 0.001 0.037 0.010 (0.017, 0.057) <0.001
Income >= $80,000 0.031 0.008 (0.016, 0.046) <0.001 0.034 0.010 (0.015, 0.053) <0.001
Race (ref: Caucasian)
- Aboriginal 0.086 0.016 (0.055, 0.117) <0.001 0.098 0.026 (0.048, 0.148) <0.001
- Others 0.022 0.011 (0.002, 0.043) 0.04 0.028 0.015 (-0.001, 0.056) 0.05
Smoking (ref: no smoker)
- Current smoker -0.026 0.013 (-0.051, -0.001) 0.04 -0.026 0.013 (0.050, -0.001) 0.04
- Past smoker -0.015 0.007 (-0.028, -0.001) 0.04 -0.015 0.008 (-0.030, 0.001) 0.07
Insulin use -0.032 0.008 (-0.048, -0.017) <0.001 -0.034 0.008 (-0.049, -0.019) <0.001
Number of medical conditions -0.027 0.002 (-0.032, -0.022) <0.001 -0.029 0.002 (-0.033, -0.024) <0.001
Intercept 0.837 0.029 (0.781, 0.893)
0.820 0.029 (0.763, 0.878)
R-squared 0.250
<0.001
Ref: reference group; PVD: peripheral vascular disease; EQ-5D-5L: Euroqol -5D Health utility index; GLM: generalized linear model; SE: standard error; 95%CI: 95% confidence
interval
89
Appendix C. Alternative models including medical conditions as dichotomous variables
C.1. Alternative regression analysis of SF-12v2 (MCS, PCS)
Variables SF-12v2 - MCS SF-12v2 - PCS
Coefficient SE 95%CI p-value Coefficient SE 95%CI p-value
Foot problems (ref: no foot problem) 0.00
- Neuropathy -1.24 0.87 (-2.94, 0.46) 0.15 -2.45 0.87 (-4.16, -0.74) 0.005
- PVD -2.36 0.58 (-3.50, -1.21) <0.001 -3.45 0.62 (-4.67, -2.23) <0.001
- Neuropathy and PVD -2.75 0.76 (-4.25, -1.26) <0.001 -4.90 0.75 (-6.38, -3.43) <0.001
- Ulcer -4.33 1.02 (-6.34, -2.32) <0.001 -7.84 1.00 (-9.79, -5.88) <0.001
- Amputation -3.24 1.52 (-6.22, -0.26) 0.03 -9.95 1.79 (-13.46, -6.44) <0.001
Age 0.17 0.02 (0.13, 0.22) <0.001 -0.01 0.02 (-0.06, 0.03) 0.62
Male 0.57 0.43 (-0.28, 1.42) 0.19 1.20 0.43 (0.36, 2.04) 0.005
Married 1.61 0.48 (0.67, 2.55) 0.001 1.49 0.48 (0.56, 2.43) 0.002
High school or more 1.81 0.55 (0.72, 2.89) 0.001 2.07 0.59 (0.92, 3.23) <0.001
Income >= $80,000 1.25 0.50 (0.27, 2.24) 0.01 2.24 0.48 (1.30, 3.18) <0.001
Race (ref: Caucasian)
- Aboriginal 2.15 1.35 (-0.49, 4.79) 0.11 4.43 1.16 (2.16, 6.70) <0.001
- Others -1.34 0.73 (-2.76, 0.08) 0.07 -0.35 0.73 (-1.78, 1.08) 0.63
Smoking (ref: no smoker) 0.00
- Current smoker -1.55 0.74 (-3.00, -0.11) 0.04 -1.46 0.72 (-2.87, -0.06) 0.04
- Past smoker 0.74 0.43 (-0.11, 1.58) 0.09 -0.14 0.42 (-0.97, 0.69) 0.74
Insulin use -1.90 0.45 (-2.78, -1.02) <0.001 -2.19 0.44 (-3.06, -1.32) <0.001
Medical conditions
- Obesity -1.21 0.43 (-2.05, -0.38) 0.004 -2.05 0.42 (-2.88, -1.22) <0.001
- Respiratory problems -1.61 0.52 (-2.64, -0.59) 0.002 -2.80 0.55 (-3.88, -1.71) <0.001
- Arthritis -2.07 0.43 (-2.90, -1.23) <0.001 -4.09 0.43 (-4,94, -3.25) <0.001
- Thyroid problems -1.34 0.52 (2.37, -0.32) 0.01 -0.60 0.53 (-1.64, 0.43) 0.25
- Cancer -0.86 0.59 (-2.02, 0.30) 0.15 -1.21 0.62 (-2.42, 0.01) 0.05
- Retinopathy -1.29 0.77 (-2.79, 0.21) 0.09 -0.47 0.75 (-1.94, 1.00) 0.53
- Kidney problems -3.10 1.06 (-5.18, -1.01) 0.004 -4.59 1.14 (-6.83, -1.35) <0.001
- Heart disease -1.10 0.55 (-2.17, -0.03) 0.04 -2.89 0.56 (-3.99, -1.79) <0.001
- Stroke -0.16 0.83 (-1.79, 1.46) 0.85 -1.67 0.88 (-3.39, 0.05) 0.06
- Dyslipidemia -0.41 0.52 (-1.42, 0.61) 0.43 -0.16 0.52 (-1.17, 0.86) 0.76
- Hypertension 0.48 0.49 (-0.47, 1.44) 0.32 -0.05 0.48 (-0.99, 0.88) 0.91
Intercept 37.64 1.72 (34.27, 41.01) 48.63 1.73
90
R-squared 0.16 0.30
Ref: reference group; PVD: peripheral vascular disease; SF-12v2: short-form-12 version 2; MCS: mental component summary; PCS: physical component summary; SE: standard
error; 95%CI: 95% confidence interval
91
C.2. Alternative regression analysis of EQ-5D-5L index and PAID-5 scores
Variables EQ-5D-5L index score PAID-5 score
Coefficient SE 95% CI p-value Coefficient SE 95% CI p-value
Foot problems (ref: no foot problem)
- Neuropathy -0.049 0.014 (-0.077, -0.020) 0.001 1.13 0.42 (0.30, 1.96) 0.01
- PVD -0.045 0.010 (-0.065, -0.026) <0.001 1.56 0.28 (1.01, 2.10) <0.001
- Neuropathy and PVD -0.105 0.016 (-0.136, -0.074) <0.001 2.23 0.39 (1.47, 2.98) <0.001
- Ulcer -0.140 0.023 (-0.185, -0.095) <0.001 2.80 0.49 (1.84, 3.77) <0.001
- Amputation -0.118 0.034 (-0.185, -0.050) 0.001 2.02 0.87 (0.32, 3.73) 0.02
Age 0.001 0.000 (0.000, 0.001) 0.07 -0.10 0.01 (-0.12, -0.08) <0.001
Male 0.013 0.007 (-0.001, 0.027) 0.08 -0.15 0.20 (-0.55, 0.25) 0.46
Married 0.008 0.008 (-0.007, 0.024) 0.31 -0.31 0.22 (-0.74, 0.13) 0.17
High school or more 0.031 0.010 (0.010, 0.051) 0.003 -0.79 0.28 (-1.34, -0.25) 0.004
Income >= $80,000 0.029 0.007 (0.015, 0.044) <0.001 -0.68 0.23 (-1.13, -0.24) 0.003
Race (ref: Caucasian)
- Aboriginal 0.082 0.016 (0.050, 0.114) <0.001 -0.80 0.58 (-1.94, 0.34) 0.17
- Others 0.017 0.011 (-0.003, 0.038) 0.10 0.94 0.42 (0.12, 1.77) 0.03
Smoking (ref: no smoker)
- Current smoker -0.026 0.012 (-0.050, -0.002) 0.03 0.13 0.36 (-0.58, 0.83) 0.73
- Past smoker -0.012 0.007 (-0.05, 0.002) 0.08 -0.38 0.20 (-0.77, 0.01) 0.06
Insulin use -0.035 0.008 (-0.050, -0.020) <0.001 1.02 0.21 (0.60, 1.43) <0.001
Medical conditions
- Obesity -0.028 0.007 (-0.041, -0.015) <0.001 0.22 0.20 (-0.17, 0.61) 0.26
- Respiratory problems -0.029 0.010 (-0.048, -0.011) 0.002 0.09 0.25 (-0.39, 0.58) 0.70
- Arthritis -0.074 0.007 (-0.088, -0.060) <0.001 0.34 0.20 (-0.05, 0.74) 0.09
- Thyroid problems -0.011 0.009 (-0.029, 0.007) 0.22 0.42 0.24 (-0.06, 0.89) 0.09
- Cancer -0.019 0.011 (-0.040, 0.003) 0.09 -0.33 0.25 (-0.83, 0.17) 0.19
- Retinopathy -0.015 0.014 (-0.043, 0.012) 0.26 0.99 0.37 (0.27, 1.71) 0.01
- Kidney problems -0.092 0.024 (-0.140, -0.045) <0.001 0.94 0.50 (-0.04, 1.92) 0.06
- Heart disease -0.016 0.010 (-0.035, 0.003) 0.10 0.08 0.26 (-0.43, 0.59) 0.75
- Stroke -0.038 0.018 (-0.072, -0.003) 0.03 0.39 0.43 (-0.46, 1.24) 0.37
- Dyslipidemia -0.002 0.008 (-0.018, 0.015) 0.84 -0.01 0.23 (-0.46, 0.45) 0.98
- Hypertension -0.005 0.007 (-0.019, 0.010) 0.53 -0.08 0.22 (-0.52, 0.35) 0.71
92
Intercept 0.825 0.030 (0.767, 0.883)
10.55 0.84 (8.89, 12.20)
R-squared 0.272
0.16
Ref: reference group; PVD: peripheral vascular disease; EQ-5D-5L: Euroqol -5D Health utility index; PAID-5: Short form of the Problem Area in Diabetes Scale; SE: standard
error; 95%CI: 95% confidence interval
93
Appendix D. Multiple regression results of models containing diabetes duration as a continuous variable
D.1. Regression results of SF-12v2 (MCS and PCS) with diabetes duration as a continuous variable
Variables SF-12v2 - MCS SF-12v2 - PCS
Coefficient SE 95%CI p-value Coefficient SE 95% CI p-value
Foot problems (ref: no foot problem)
- Neuropathy -0.70 0.90 (-2.47, 1.06) 0.44 -3.09 0.97 (-4.99, -1.20) 0.001
- PVD -2.50 0.66 (-3.80, -1.21) <0.001 -3.55 0.70 (-4.93, -2.17) <0.001
- Neuropathy and PVD -2.73 0.81 (-4.32, -1.14) 0.001 -5.02 0.85 (-6.69, -3.36) <0.001
- Ulcer -5.37 1.24 (-7.80, -2.93) <0.001 -9.21 1.25 (-11.66, -6.76) <0.001
- Amputation -3.67 1.71 (-7.03, -0.31) 0.03 -8.06 2.15 (-12.28, -3.85) <0.001
Age 0.21 0.03 (0.16, 0.26) <0.001 0.01 0.03 (-0.04, 0.06) 0.59
Male 0.74 0.49 (-0.21, 1.69) 0.13 1.15 0.47 (0.21, 2.08) 0.02
Married 1.70 0.55 (0.61, 2.79) 0.002 1.33 0.56 (0.23, 2.43) 0.02
High school or more 1.80 0.62 (0.58, 3.01) 0.004 2.97 0.68 (1.64, 4.30) <0.001
Income >= $80,000 1.05 0.58 (-0.08, 2.19) 0.07 2.16 0.55 (1.09, 3.23) <0.001
Race (ref: Caucasian) 0.00
- Aboriginal 1.06 1.50 (-1.89, 4.01) 0.48 3.33 1.35 (0.67, 5.99) 0.01
- Others -1.17 0.99 (3.12, 0.78) 0.24 0.08 0.93 (-1.74, 1.91) 0.93
Smoking (ref: no smoker) 0.00
- Current smoker -0.60 0.80 (-2.17, 0.97) 0.45 -0.93 0.81 (-2.53, 0.66) 0.25
- Past smoker 0.96 0.49 (0.00, 1.93) 0.05 -0.08 0.48 (-1.03, 0.86) 0.86
Insulin use -1.81 0.52 (-2.84, -0.78) <0.001 -2.04 0.52 (-3.06, -1.01) <0.001
Diabetes duration -0.02 0.02 (-0.07, 0.02) 0.31 -0.02 0.02 (-0.06, 0.03) 0.53
Number of medical conditions -1.13 0.16 (-1.44, -0.82) <0.001 -1.89 0.16 (-2.20, -1.59) <0.001
Intercept 36.82 1.87 (33.16, 40.48)
48.55 1.90 (44.82, 52.28)
R-squared 0.16
0.27
Ref: reference group; PVD: peripheral vascular disease; SF-12v2: short-form-12 version 2; MCS: mental component summary; PCS: physical component summary; SE: standard
error; 95%CI: 95% confidence interval
94
D.2. Regression results of EQ-5D-5L index and PAID-5 scores with diabetes duration as a continuous variable
Variables EQ-5D-5L index score PAID-5 score
Coefficient SE 95%CI p-value Coefficient SE 95% CI p-value
Foot problems (ref: no foot problem)
- Neuropathy -0.051 0.015 (-0.080, -0.021) <0.001 1.15 0.45 (0.27, 2.03) 0.01
- PVD -0.047 0.012 (-0.069, -0.024) <0.001 1.57 0.31 (0.96, 2.17) <0.001
- Neuropathy and PVD -0.102 0.017 (-0.135, -0.069) <0.001 2.22 0.42 (1.41, 3.04) <0.001
- Ulcer -0.164 0.028 (-0.218, -0.110) <0.001 2.70 0.56 (1.61, 3.80) <0.001
- Amputation -0.111 0.043 (-0.195, -0.027) 0.01 1.66 0.93 (-0.17, 3.48) 0.08
Age 0.001 0.000 (0.000, 0.002) 0.01 -0.09 0.01 (-0.12, -0.07) <0.001
Male 0.013 0.008 (-0.002, 0.029) 0.09 -0.32 0.21 (-0.74, 0.10) 0.14
Married 0.012 0.009 (-0.006, 0.031) 0.19 -0.33 0.24 (-0.80, 0.14) 0.17
High school or more 0.043 0.012 (0.019, 0.068) <0.001 -0.60 0.30 (-1.20, 0.00) 0.05
Income >= $80,000 0.026 0.009 (0.009, 0.043) 0.00 -0.48 0.25 (-0.98, 0.02) 0.06
Race (ref: Caucasian)
- Aboriginal 0.066 0.019 (0.029, 0.102) <0.001 -0.47 0.67 (-1.78, 0.83) 0.48
- Others 0.026 0.013 (0.001, 0.052) 0.05 0.45 0.50 (-0.53, 1.44) 0.37
Smoking (ref: no smoker)
- Current smoker -0.020 0.014 (-0.048, 0.007) 0.15 -0.10 0.39 (-0.86, 0.66) 0.79
- Past smoker -0.012 0.008 (-0.027, 0.003) 0.13 -0.38 0.22 (-0.81, 0.04) 0.08
Insulin use -0.034 0.009 (-0.052, -0.017) <0.001 1.15 0.24 (0.69, 1.61) <0.001
Diabetes duration 0.000 0.000 (-0.001, 0.001) 0.76 0.00 0.01 (-0.02, 0.02) 0.82
Number of medical conditions -0.025 0.003 (-0.030, -0.019) <0.001 0.16 0.07 (0.01, 0.30) 0.03
Intercept 0.799 0.032 (0.735, 0.862)
9.83 0.93 (8.00, 11.66)
R-squared 0.232
0.13
Ref: reference group; PVD: peripheral vascular disease; EQ-5D-5L: Euroqol -5D Health utility index; PAID-5: Short form of the Problem Area in Diabetes Scale; SE: standard
error; 95%CI: 95% confidence interval
95
Appendix E. Characteristics of participants with and without missing values of
diabetes duration
Outcome Included (1,935)
Diabetes
duration (1,479)
Missing diabetes
duration (456) p-value
Age - mean (sd) 64.5 (10.7) 64.7 (10.3) 64.0 (11.8) 0.25
Gender - n(%)
- Female 875 (45.2) 683 (46.2) 192 (42.1) 0.13
- Male 1,060 (54.8) 796 (53.8) 264 (57.9)
Marital Status - n(%)
- Married 1,379 (71.3) 1073 (72.5) 306 (67.1) 0.02
- Not Married 556 (28.7) 406 (27.5) 150 (32.9)
Education - n(%)
- Less than high school 285 (14.7) 204 (13.8) 81 (17.8) 0.04
- High School or more 1,650 (85.2) 1,275 (86.2) 375 (82.2)
Ethnicity - n(%)
- Caucasian 1,752 (90.5) 1,374 (92.9) 378 (82.9) <0.001
- Aboriginal 46 (2.4) 35 (2.4) 11 (2.4)
- Others 137 (7.1) 70 (4.7) 67 (14.7)
Annual household income - n(%)
- <$80,000 1,481 (76.5) 1,119 (75.7) 362 (79.4) 0.1
- >=$80,000 454 (23.5) 360 (24.3) 94 (20.6)
Insulin use - n(%) 667 (34.5) 495 (33.5) 172 (37.7) 0.09
Foot problems
0.17
- No foot problems 1,214 (62.7) 939 (63.5) 275 (60.3)
- Neuropathy 123 (6.4) 98 (6.6) 25 (5.5)
- PVD 287 (14.8) 212 (14.3) 75 (16.4)
- Neuropathy and PVD 186 (9.6) 144 (9.7) 42 (9.2)
- Ulcer 97 (5.0) 69 (4.7) 28 (6.1)
- Amputation 28 (1.4) 17 (1.1) 11 (2.4)
Number of medical conditions - mean
(sd) 3.54 (1.6) 3.54 (1.6) 3.56 (1.8) 0.85
- Dyslipidemia - n(%) 1,558 (80.5) 1,029 (69.6) 292 (64.0) 0.03
- Obesity - n(%) 1,093 (56.5) 835 (56.5) 258 (56.6) 0.96
- Respiratory problems - n(%) 368 (19.0) 286 (19.3) 82 (18.0) 0.52
- Arthritis - n(%) 952 (49.2) 733 (49.6) 219 (48.0) 0.57
- Thyroid Problem - n(%) 426 (22.0) 338 (22.8) 88 (19.3) 0.11
- Cancer - n(%) 262 (13.5) 200 (13.5) 62 (13.6) 0.97
- Retinopathy - n(%) 161 (8.3) 111 (7.5) 50 (11.0) 0.02
- Kidney Failure - n(%) 86 (4.4) 60 (4.1) 26 (5.7) 0.14
- Heart disease - n(%) 384 (19.8) 280 (18.9) 104 (22.8) 0.07
- Hypertension - n(%) 1,433 (74.1) 1,103 (74.6) 330 (72.4) 0.35
- Stroke - n(%) 135 (7.0) 93 (6.3) 42 (9.2) 0.03
Smoking - n(%)
- Never 793 (41.0) 592 (40.0) 201 (44.1) 0.27
96
- Current Smoker 199 (10.3) 152 (10.3) 47 (10.3)
- Quit smoking 943 (48.7) 735 (49.7) 208 (45.6)
PAID-5 score - mean (sd) 4.32 (4.3) 4.08 (4.1) 5.11 (4.9) <0.001 PAID-5: Short form of the Problem Area in Diabetes Scale; sd: standard deviation
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